On this page:

• Overview
• Bebtelovimab
• Tixagevimab/Cilgavimab (Evusheld)
• Previously Efficacious Monoclonal Antibodies
  • Bamlanivimab/Etesevimab
  • Casirivimab/Imdevimab
  • Sotrovimab
• Resources
• Multimedia

Last reviewed: August 4, 2022

Overview

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 immunizing mice genetically modified to have a humanized immune system and harvesting effective antibodies from them (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 direct antiviral monoclonal antibody products under development for SARS-CoV-2 target the spike protein, which the virus utilizes to enter host cells, thus blocking viral attachment and entry into human cells (Marovich, June 2020). Products that have received FDA authorization include bamlanivimab/etesevimab, casirivimab/imdevimab (brand name REGEN-COV) and sotrovimab. However, because the Omicron variant has become the dominant variant in the United States, bebtelovimab is the only monoclonal antibody currently recommended for use to treat COVID-19. Additionally, tixagevimab/cilgavimab (brand name Evusheld) is emergency-authorized as pre-exposure prophylaxis against COVID-19 for immunocompromised individuals or those who cannot be vaccinated or mount post-vaccination immune response.

Bebtelovimab

In February 2022, FDA issued an emergency use authorization for bebtelovimab for the treatment of mild to moderate COVID-19 in adults and certain pediatric patients over the age of 12 for whom alternative treatment options are not accessible or clinically appropriate.

Available in vitro data from both pseudotyped virus-like particle and authentic SARS-CoV-2 virus neutralization testing shows that this monoclonal antibody retains neutralization efficacy against all variants of SARS-CoV-2 except Mu. It retains efficacy against the Omicron variant of SARS-CoV-2, including BA.1.1.529, BA.1.1 and BA.2, BA.4, and BA.5 (FDA Fact Sheet for Health Care Providers, June 2022).

Clinical data for its EUA authorization came from the BLAZE-4 trial, which was performed prior to the era when Omicron was a dominant strain (50% of participants had Delta, and 29% had Alpha). BLAZE-4 was a Phase 2 study that enrolled both low risk and high risk nonhospitalized participants with mild to moderate COVID-19 and examined clinical efficacy of 175 mg bebtelovimab alone and combined with bamlanivimab/etesevimab compared to placebo in preventing hospitalization or death, when administered within 3 days of testing positive.

The study design was complex, with many arms, and included a randomized portion and an open-label portion. One notable difference between the treatment groups was that more participants in the placebo arm were seropositive at baseline than in the group receiving bamlanivimab/etesevimab/bebtelovimab together or the group receiving bebtelovimab alone (15%, 9% and 7%, respectively); all participants were unvaccinated. A nonclinical, virologic primary endpoint of persistently high viral load by day 7 was chosen.

A persistently high viral load was observed in 21%, 13% and 14% of participants in the placebo, combination monoclonal antibody and bebtelovimab groups, respectively. The secondary endpoint of COVID-19-related hospitalization or death by day 29 was observed in 1.6%, 2.4% and 1.6% of those three groups, respectively.

Tixagevimab/Cilgavimab

Tixagevimab/cilgavimab (brand name EVUSHELD; AZD7442) is a long-acting monoclonal antibody combination that has been FDA-authorized for emergency use as pre-exposure prophylaxis for prevention of COVID-19 in certain immunocompromised adults and pediatric patients since December 2021 (dosing was revised in February 2022).

Although the combination was highly active against earlier SARS-CoV-2 variants, in October 2022 FDA announced that individuals receiving tixagevimab/cilgavimab face an increased risk for developing COVID-19 when exposed to novel variants of SARS-CoV-2 that evade neutralization because tixagevimab has no activity against circulating BA.4/BA.5 subvariants, while cilgavimab has reduced activity (see table).

IDSA guidelines continue to suggest pre-exposure prophylaxis with tixagevimab/cilgavimab rather than no tixagevimab/cilgavimab in moderately or severely immunocompromised individuals at increased risk for inadequate immune response to COVID-19 vaccine or for whom COVID-19 vaccine is not recommended due to a documented serious adverse reaction to the vaccine (conditional recommendation, low certainty of evidence).

Based on current U.S. variant prevalence, NIH guidelines continue to recommend tixagevimab/cilgavimab as pre-exposure prophylaxis for patients who are moderately to severely immunocompromised and may have inadequate immune response to COVID-19 vaccination (BIIa) or are not able to be fully vaccinated with any available COVID-19 vaccines due to a documented history of severe adverse reaction to a COVID-19 vaccine or any of its components (AIIa).

Frequently Asked Questions

What is the evidence on tixagevimab/cilgavimab for pre-exposure prevention of COVID-19?

Pre-exposure prophylaxis was compared to placebo in 5,197 participants (75% of whom had comorbidities increasing risk of severe disease) who did not have SARS-CoV-2 infection at baseline. The study found thatThe FDA emergency use authorization of tixagevimab/cilgavimab for PrEP was largely based on the PROVENT study (Levin, June 2022), a randomized, placebo-controlled phase III clinical trial that examined whether lower dose tixagevimab/cilgavimab (150 mg/150 mg) given before exposure was protective against symptomatic COVID-19 when administered to largely immunocompetent, unvaccinated adults in the pre-Omicron variant era. Compared to placebo in 5,197 participants (75% of whom had comorbidities increasing risk of severe disease) who did not have SARS-CoV-2 infection at baseline, the study found that participants in the treatment group had a lower risk of developing symptomatic COVID-19, with a relative risk reduction of 77% (95% CI, 46%-90%).

Why did FDA recommend a tixagevimab/cilgavimab dosing change?

The tixagevimab/cilgavimab FDA EUA was revised in February 2022 to increase the initial dosing of tixagevimab/cilgavimab for pre-exposure prophylaxis from 150 mg/150 mg to 300 mg/300 mg due to observed decrease in in vitro activity against Omicron BA.1 subvariants.

The drug’s manufacturer, AstraZeneca, is also conducting an additional dose-ranging study of the safety, immunogenicity, pharmacokinetics/pharmacodynamics and efficacy of the following dosing regimens (data not yet available):

• 300 mg tixagevimab and 300 mg cilgavimab administered as two consecutive IM injections, followed 3 months later by 150 mg tixagevimab and 150 mg cilgavimab administered as two consecutive IM injections, with subsequent redosing every 3 months.
• 600 mg tixagevimab and 600 mg cilgavimab administered as an IV infusion followed 6 months later by 300 mg tixagevimab and 300 mg cilgavimab administered as two consecutive IM injections followed by redosing every 6 months.

Individuals who have not yet received tixagevimab/cilgavimab but could benefit from administration are recommended to receive 300 mg tixagevimab and 300 mg cilgavimab as a first dose. Individuals who initially received the previously authorized 150 mg/150 mg dose should receive a second 150 mg/150 mg dose as soon as possible.

What timing considerations should be considered when prescribing a follow-up or repeat Evusheld dose?

No safety and efficacy data exist to inform ideal timing of repeat dosing. Drug levels and duration of effectiveness in the PROVENT study, however, suggested a duration of effect of 6 months in the pre-Omicron era. As such, FDA currently recommends repeat dosing at 6 months, while noting that due to uncertainty of the variant landscape revisions to dosing schedules may be required.

Is tixagevimab/cilgavimab effective after COVID exposures to prevent symptomatic illness as post-exposure prophylaxis (PEP)?

In the STORM CHASER study of tixagevimab/cilgavimab for PEP, the safety and efficacy at preventing symptomatic COVID-19 of a 150 mg/150 mg intramuscular dose was compared to that of placebo among 1,121 unvaccinated participants with recent (≤8 days) exposure to an individual with laboratory-confirmed COVID-19. The primary endpoint (which was not met) was the prevention of PCR-confirmed symptomatic COVID-19 up to day 183 post treatment; participants were followed for 15 months. There was a nonsignificant reduction in the overall study population of the risk of symptomatic COVID-19 by 33% (95% CI, 26%-65%) in the treatment arm compared to placebo (rates were 3% [23/749] and 4.6% [17/372], respectively).

In a pre-planned subgroup analysis among only those participants confirmed to be PCR-negative at baseline, there was a 73% reduction (95% CI, 27%-90%) in symptomatic COVID-19 cases in the tixagevimab/cilgavimab treatment group compared to placebo (0.8% [6/715] and 3% [11/358] respectively). When looking only at COVID-19 cases that occurred more than 7 days after dosing (most likely to represent cases acquired while on the drug as opposed to before the drug had been given), the effect was stronger: a 92% reduction (95% CI, 32%-99%) in symptomatic COVID-19 cases in the treatment group as compared to placebo (0.1% [1/710] and 1.6% [6/353], respectively). In summary, the drug combination was not found to be significantly effective in humans as post-exposure prophylaxis, potentially due to a delay in achieving drug levels via the intramuscular route (Loo, January 2022).

Were immunocompromised people included in the PrEP trials of tixagevimab/ cilgavimab?

Notably, clinical trials data specific to immunocompromised populations remain limited – only approximately 3% of PROVENT participants were receiving immunosuppressive therapy – though several cohort studies have detailed the immunogenicity and real-world effectiveness of tixagevimab/cilgavimab as pre-exposure prophylaxis against Omicron sublineages (see question below).

What are the real-world effectiveness data for tixagevimab/cilgavimab in immunocompromised people?

Several observational studies have evaluated the effectiveness of tixagevimab/cilgavimab against SARS-CoV-2 infection in immunocompromised people. General considerations for interpreting these data include the tested population (degree of immunocompromise, vaccination status, comorbidities), identification of a matched control group, as well as the predominant variant circulating during follow up (i.e., the most prevalent Omicron sublineage).

An early effectiveness study in kidney transplant recipients using lower-dose (150 mg/150 mg) tixagevimab/cilgavimab amid the French BA.1 wave showed high rates of clinically significant COVID-19 despite prophylaxis (Benotmane, June 2022). However, when later compared to an “unprotected” group of transplant recipients during the BA.1 and BA.2 waves, recipients of tixagevimab/cilgavimab pre-exposure prophylaxis experienced fewer SARS-CoV-2 infections and severe COVID-19 outcomes. Similarly, a large study of a mixed population of immunocompromised people in Israel during the BA.2 wave (Bertrand, August 2022) showed 50% reduction in SARS-CoV-2 infections in adjusted analysis following 150 mg/150 mg tixagevimab/cilgavimab prophylaxis. In the U.S., tixagevimab/cilgavimab also showed good effectiveness in a diverse cohort of organ transplant recipients during the BA.1 and BA.2 waves; specifically, infection rates were 3-fold higher in the control group. However, tixagevimab/cilgavimab breakthroughs were observed in patients receiving lower drug dosing and among lung transplant recipients.

There are no published data at present on the effectiveness of tixagevimab/cilgavimab during the BA.4/5 era. Additionally, the durability of protection against these and other variants as drug levels wane remains uncertain. Based on upon pharmacokinetic modeling data, FDA currently recommends repeat dosing of 300 mg/300 mg tixagevimab/cilgavimab every 6 months.

What is the neutralizing activity of tixagevimab/cilgavimab against Omicron sublineages?

Although potently active against SARS-CoV-2 variants in the pre-Omicron era, there are significant reductions in neutralization of Omicron variants by tixagevimab and to a less extent cilgavimab, which is heavily influenced by the spike protein sequence of the unique sublineage (Wang, July 2022). Several studies confirm that BA.1 sublineages evade tixagevimab/cilgavimab neutralization (100-400-fold reduction in antibody titer) (Takashita, August 2022). This includes studies using sera from previously vaccinated, immunocompromised people given tixagevimab/cilgavimab pre-exposure prophylaxis (Bruel, March 2022). Notably, increased drug dosing from 150 mg/150 mg to 300 mg/300 mg may augment short-term neutralizing capacity in some immunocompromised populations (Benotmane, August 2022; Stuver, May 2022; Karaba, May 2022 – preprint, not peer-reviewed). In contrast, many BA.2 sublineages demonstrate good in vitro sensitivity to tixagevimab/cilgavimab, with neutralizing antibody detected several months following injection (Benotmane, August 2022; Bruel, August 2022 – preprint, not peer-reviewed). Emerging BA.2.75 sublineage may be an exception, exhibiting further immune evasion, though results from in vitro studies are mixed (Sheward, September 2022; Takashita, September 2022).

Relevant to the current variant climate, tixagevimab/cilgavimab does appear to neutralize BA.4/5 sublineages, with a degree of immune evasion intermediate between that of BA.1 and BA.2. Data regarding BA.4/5 neutralization following tixagevimab/cilgavimab injection in immunocompromised people, however, are limited; one unpublished study in people with autoimmune disease indicates that neutralizing antibody may persist for 4-5 months post injection (Bruel, August 2022 – preprint, not peer-reviewed). Certain BA.4/5 sublineages such the BA.4.6 subvariant exhibit additional mutations (e.g., at position 346) (Wang, September 2022 – preprint, not peer-reviewed), which may further impair tixagevimab/cilgavimab activity (Jian, September 2022). Additionally, emerging data indicate accumulated mutations in BA.2 and BA.5 sublineages such as BQ.1.1 show significant evasion of multiple antibodies including tixagevimab/cilgavimab (Bertrand, August 2022).

What is the evidence for tixagevimab/cilgavimab as treatment of symptomatic COVID-19?

Two randomized clinical trials of higher-dose (300 mg/300 mg) tixagevimab/cilgavimab have evaluated tixagevimab/ cilgavimab for treatment of COVID-19.

In the randomized, placebo-controlled TACKLE trial, a reduction in mortality was seen with 300 mg/300 mg intramuscular injection given to outpatients in early disease (Montgomery, June 2022). The combined endpoint of severe illness or death occurred in 18 (4%) of 407 participants in the tixagevimab/cilgavimab group versus 37 (9%) of 415 participants given placebo (RRR 50.5% [95% CI, 14.6-71.3]; p=0.0096); absolute risk reduction 4.5% (95% CI, 1.1-8.0; p<0.0001).

The ACTIV-3 study of intravenous 300 mg/300 mg dosing in hospitalized people found modestly lower mortality (61/710 [9%] in the tixagevimab/cilgavimab group versus 86/707 [12 %] in the placebo group; hazard ratio [HR] 0.70 [95% CI, 0.50-0.97]; p=0.032) (ACTIV-3 Study Group, July 2022). In ACTIV-3, a similar time to sustained recovery was seen in the two groups. These findings contributed to authorization of tixagevimab/cilgavimab for treatment of symptomatic COVID-19 in non-hospitalized patients in the European Union and in Canada; the FDA EUA, in contrast, currently restricts its use solely to the pre-exposure setting.

A recently presented post-hoc analysis of the TACKLE trial looked at the effect of tixagevimab/cilgavimab versus placebo on self-reported symptom severity and time to symptom resolution over a month (Campos IDWeek Presentation, October 2022). There was a significantly lower rate of symptom progression through day 29 in the tixagevimab/ cilgavimab group than the placebo group (55.7% versus 63.4%; RRR 12.5%; p=0.041.) There was also a significant improvement in overall symptom severity and an improved time to symptom resolution in the tixagevimab/cilgavimab groups as compared to placebo.

What are the safety data for use of tixagevimab/cilgavimab?

The PROVENT trial, comprised mainly of immunocompetent people, did not detect statistically significant differences in serious adverse events between the tixagevimab/cilgavimab arm and the placebo arm. There was, however, a numerical imbalance for cardiovascular events observed in the tixagevimab/cilgavimab arm (23/3,461 [0.7%] versus 5/1,736 [0.3]). Events occurred throughout the follow up period and included myocardial infarction, heart failure, and arrhythmia, all among people with either prior cardiac risk factor or known history. A causal relationship is uncertain, though FDA EUA materials recommend risk-benefit discussions for people at high risk for cardiovascular disease. There was a low incidence of hypersensitivity reaction with tixagevimab/cilgavimab (1 anaphylactoid event among 3,461 recipients [<0.1%]).

Small observational studies among immunocompromised populations have not reported a signal for severe adverse events such as alloimmune complications (e.g., organ rejection) or cardiovascular disease (Jurdi, June 2022). As with other authorized therapies, clinical experience submitted by patients and providers will be reviewed by FDA for potential safety signals.

Previously Efficacious Monoclonal Antibodies

Note: Information on previously efficacious but no longer available anti-SARS-COV-2 monoclonal antibodies is provided below, but it is important to note that many do NOT retain efficacy against the currently circulating variants of SARS-CoV-2. For an up-to-date encapsulation of regional variant frequency, refer to CDC’s COVID Data Tracker for recent proportions of circulating variants based on the national genomic surveillance system. For up-to-date information on whether a given monoclonal antibody retains efficacy against a given variant and is therefore still authorized in the U.S., refer to FDA’s EUA hub.

Bamlanivimab/Etesevimab

Eli Lilly’s monoclonal antibody bamlanivimab (also known as LY-CoV555, aka LY3819253) was originally derived from the blood of one of the first U.S. patients who recovered from COVID-19. It is a recombinant neutralizing monoclonal antibody directed against the SARS-CoV-2 spike protein. Eli Lilly’s etesevimab (LY-CoV016, aka JS016, aka LY3832479) is a monoclonal antibody directed against the SARS-CoV-2 surface spike protein’s receptor binding domain.

Casirivimab/Imdevimab 

Regeneron’s REGEN-COV (previously known as REGN-CoV2 or REGEN-CoV2) consists of two antibodies that bind to different regions of the SARS-CoV-2 spike protein receptor binding domain: casirivimab (REGN10933) and imdevimab (REGN10987). In October 2020, an independent data monitoring committee recommended halting a study examining the use of casirivimab plus imdevimab in hospitalized patients requiring high-flow oxygen or mechanical ventilation, due to a potential safety signal and an unfavorable risk/benefit profile.

However, in outpatients, two double-blind, randomized, controlled trials of REGEN-COV (trials 2067 and 20145; also see Weinreich, 2021, an interim analysis) have recently released results via press release. In study 20145 (N=803), an outpatient dose-ranging virologic efficacy trial of REGEN-COV among low-risk outpatients with asymptomatic or mild symptomatic COVID-19, there was comparable viral load drop among all dose levels, including the subcutaneously dosed groups, through day 7 (without a dose-response effect). In the large outpatient study of the impact of REGEN-COV on clinical outcomes among high-risk patients with COVID-19 (N=4,567), there was a significant reduction in COVID-related hospitalization or death of 71.3% (1.3% vs. 4.6%; p<0.0001) in the 2,400 mg group and 70.4% (1.0% vs. 3.2%) in the 1,200 mg group, as compared to placebo. The effect was strongest among those with baseline SARS-CoV-2 viral load above 1 million and negative SARS-CoV-2 antibodies. Likewise, the time to symptom resolution was faster with both doses than placebo, with a median of 10 versus 14 days to clinical improvement (p<0.0001). In a large safety database of participants from these two trials (N=6,334), no serious safety signal of concern was observed, and severe adverse events were less frequent in the combined monoclonal antibody group than in the placebo group (1.4% vs. 4%). The large, Phase 3 U.K. NHS RECOVERY trial then evaluated REGEN-COV in a very large (N=9,785) group of patients hospitalized with COVID-19, and found that, among participants who were seronegative for SARS-CoV-2 at baseline, there was a significant mortality benefit from receiving the combination of casirivimab and imdevimab (REGEN-COV), as compared to standard of care (see Key Literature, below).

REGEN-COV has also been studied as a “passive vaccine” in study 2069 to prevent infection among household contacts of patients with known COVID. Final Phase 3 results are forthcoming and showed a reduction in symptomatic (SARS-CoV-2 PCR+) infections from 8/233 (3.6%) in placebo to 0/186 (0%) in REGEN-COV group (p<0.01). There was also a reduction in SARS-CoV-2 PCR+ infections of any symptom degree with a high (above 10,000) viral load, from 13/212 (6.1%) in the placebo group to 0/179 (0%) in the REGEN-COV group (p<0.001).

In November 2020, FDA granted emergency use authorization for both bamlanivimab and the combination of casirivimab and imdevimab in outpatients with mild to moderate COVID-19 who are at high risk for severe COVID-19. These approvals were based on interim analyses of outpatient randomized controlled trials, which showed a reduction in COVID-19 related hospitalization or emergency room visits with the use of these monoclonal products. Following these two trials, the randomized controlled ACTIV-3 study of bamlanivimab in hospitalized COVID-19 patients without end-organ failure showed little additional impact on sustained recovery over 90 days when compared to placebo plus standard of care, which included remdesivir and corticosteroids (Gottlieb, January 2021). The study was stopped by the data safety and monitoring board for futility after 314 participants had been enrolled.

Sotrovimab

In May 2021, FDA approved for emergency use a new monoclonal anti-SARS-CoV-2 antibody manufactured by GSK and Vir Biotechnology, sotrovimab (formerly VIR-7831), which binds to a highly conserved epitope of the receptor binding domain of viral spike protein. The approval was based on an analysis of data from the COMET-ICE study, a randomized controlled trial investigating the safety and efficacy of sotrovimab 500 mg IV given within 5 days of symptom onset in 583 nonhospitalized adults with mild to moderate SARS-CoV-2 infection. The primary endpoint, death or >24 hours of hospitalization through day 29 after dose, was reached in 21 of 292 (7%) patients in the placebo group compared to 3 of 291 (1%) who received sotrovimab, an 85% reduction (p=0.002). Based on these results at the time of the interim analysis, an independent safety and data monitoring committee recommended stopping the study. A parallel in vitro study found that sotrovimab retains efficacy against most circulating variants. Further studies are planned by the manufacturers, including a pharmacokinetic study (COMET-PEAK) comparing venous and intramuscular sotrovimab, which could lay the groundwork for intramuscular administrations of anti-SARS-CoV-2 monoclonal antibodies, rather than intravenous infusions; this will be followed by Phase 3 trials assessing the impact of intramuscular sotrovimab on hospitalization and death in high-risk people with COVID-19 and on symptomatic infection among asymptomatically infected individuals (COMET-TAIL and COMET-STAR).

Resources

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