Last reviewed: June 14, 2021
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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 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 (Marovich, June 2020), thus blocking viral attachment and entry into human cells. Products farthest along in clinical trials have been created by Eli Lilly and Regeneron. 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 etesivumab (LY-CoV016, aka JS016, aka LY3832479) is a monoclonal antibody directed against the SARS-CoV-2 surface spike protein’s receptor binding domain. 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=4567), 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-CoV2 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=6334), no serious safety signal of concern was observed, and SAEs were less frequent in the combined monoclonal antibody group than in the placebo group (1.4% vs. 4%). Finally, the REGEN-COV combination is also under study in the Phase 3 U.K. NHS RECOVERY trial, with a primary endpoint of mortality.
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.
In February 2021, FDA granted emergency use authorization for the combination of bamlanivimab and etesevimab for the treatment of mild to moderate COVID-19 in non-hospitalized patients who are at high risk for progressing to severe disease. (These products are not authorized for people who are hospitalized due to COVID-19 or require oxygen due to COVID-19.) The approval was based on an interim analysis of the Phase 3 BLAZE-1 clinical trial announced via press release and now published (Gottlieb, January 2021). The study included 1,035 ambulatory patients with mild to moderate COVID-19 at risk for progression to severe disease; 518 received the monoclonal antibody product, and 517 received placebo. Of these, 2% (11) patients in the monoclonal antibody arm required hospitalization or died, while 7% (36) patients in the placebo arm required hospitalization or died, resulting in a 70% risk reduction of hospitalization or death (p=0.0004).
In March 2021, FDA advised in an updated bamlanivimab EUA that providers consider its use in combination with other monoclonal antibodies that retain activity against circulating variant strains of SARS-CoV-2. The updated EUA included a table describing susceptibility of variant strains of SARS-CoV-2 to the combination of bamlanivimab and etesivimab. On March 24, 2021, the U.S. Department of Health and Human Services’ Assistant Secretary for Preparedness and Response issued a notice that the government will stop the distribution of bamlanivimab alone, out of concern for a sustained increase in variants of SARS-CoV-2 with resistance to bamlanivimab monotherapy.
At the 2021 Conference on Retroviruses and Opportunistic Infections (CROI), data was presented from the BLAZE-2 trial on bamlanivimab for the prevention of severe disease among residents and staff of long-term care facilities, a population accounting for 37% of COVID-19 deaths in the U.S (Cohen, March 2021). The study found in 966 participants that infusion of bamlanivimab reduced symptomatic and severe COVID-19 infection by 80% when compared to placebo (8.8% compared to 22.5%; OR, 0.20 [.08-0.49]; p<0.001). This effect held true for the subpopulation at high risk for severe disease (the residents) with 72% lower odds of getting mild or worse disease (OR, 0.28 [0.15-0.53]; p<0.001). Among those participants who did become infected, there was a lower average viral load and more precipitous drop in average SARS-CoV-2 viral load in the bamlanivimab than the placebo group.
Early in the pandemic, there was a recognition that certain cytokines (including IL-6, CXCL-10 and GM-CSF) occur at much higher levels in COVID-19 patients with severe disease than with mild disease; similarly, levels were higher in patients who died from COVID-19 (Thwaites, March 2021; Henry, June 2020). The cytokine GM-CSF in particular is 10-fold higher in people who died from COVID-19 than people with mild COVID. Because it is upstream in the cascade of cytokine release, it was theorized that blocking GM-CSF would provide more benefit in blocking a hyperinflammatory response to SARS-CoV-2 infection than blocking individual cytokines, such as IL-6.
Based on this, a monoclonal antibody targeting GM-CSF, lenzilumab (Humanigen), was tested under emergency IND in a small cohort of patients (N=12) who were hospitalized with severe COVID-19 pneumonia, and its outcomes were compared to the outcomes of a matched control cohort (Temesgen, November 2020). The study found that time to clinical improvement was significantly shorter for the lenzilumab-treated group compared with the untreated cohort, with a median of 5 days versus 11 days (P=.006). There was also a significant difference in the oxygenation status, as measured by change in mean oxygen saturation (SpO2)/fraction of inspired oxygen (Fio2) ratio from baseline (day 0) through day 14 post-therapy, between the two groups (ANOVA p<0.001), and in the percentage of patients with acute respiratory distress syndrome (defined as SpO2/Fio2 <315 mm Hg) (ANOVA p<0.001). In addition, another monoclonal antibody binding the GM-CSF receptor, mavrilimumab, was associated with oxygenation improvement and shorter hospitalization in a small cohort of hospitalized patients, and the anti-GM-CSF monoclonal antibodies, TJ003234 and regimsilumab, are also being studied.
In parallel, otilimab, another anti-GM-CSF agent currently in Phase 3 studies for rheumatoid arthritis, was studied in a Phase 2 study in patients with severe COVID-related pulmonary disease. It missed meeting its primary endpoint of significant clinical improvement, but showed a significant benefit in a subgroup of 180 older patients (over age 70), with respect to both respiratory improvement and death; currently, the study is enrolling 350 more older patients, with results forthcoming. Lenzilumab has received FDA approval for compassionate use in the COVID-19 setting. Prospective randomized controlled studies are ongoing and will provide more information on clinical benefit from these agents.
Among ambulatory care patients, IDSA guidelines suggest the use of bamlanivimab/etesivimab or casirivimab/imdevimab in patients with mild to moderate COVID-19 who are at high risk for progression to severe disease. Patients who are admitted to the hospital for reasons other than COVID-19, and who have mild-moderate COVID-19, may also receive these therapies.
FDA's EUA defines high-risk patients as meeting at least one of the following criteria:
- Have a body mass index ≥35;
- Have chronic kidney disease;
- Have diabetes;
- Have immunosuppressive disease;
- Are currently receiving immunosuppressive treatment;
- Are ≥65 years of age;
- Are ≥55 years of age AND have cardiovascular disease, OR hypertension OR chronic obstructive pulmonary disease/other chronic respiratory disease;
- Are 12–17 years of age AND have BMI ≥85th percentile for their age and gender based on CDC growth charts, OR sickle cell disease, OR congenital or acquired heart disease, OR neurodevelopmental disorders, for example, cerebral palsy, OR a medical-related technological dependence, for example, tracheostomy, gastrostomy, or positive pressure ventilation (not related to COVID-19), OR asthma, reactive airway or other chronic respiratory disease that requires daily medication for control.
Among hospitalized patients with severe COVID-19, IDSA recommends against bamlanivimab monotherapy.
NIH guidelines recommend the use of bamlanivimab 700 mg plus etesevimab 1,400 mg OR casirivimab 1,200 mg plus imdevimab 1,200 mg for outpatients with mild to moderate COVID-19 who are at high risk of clinical progression.
NIH recommends against the use of monoclonal antibodies in patients who are hospitalized because of COVID-19, except in a clinical trial. However, they state the combination 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.
Effect of Bamlanivimab as Monotherapy or in Combination with Etesevimab on Viral Load in Patients with Mild to Moderate COVID-19 (BLAZE-1) (Gottlieb, January 2021).
Overall, in this small study of dose-escalating bamlanivimab monotherapy versus combination bamlanivimab/etesivimab therapy, combination therapy was seen to reduce day 11 SARS-CoV-2 viral load. Treatment-emergent resistance was observed with all monotherapy groups. Post hoc analyses suggest that older and/or obese patients may have had lower hospitalization rates when treated early with combination therapy compared to placebo.
- 613 COVID-19 patients who tested positive for SARS-CoV-2 (direct antigen or PCR tests), were within 3 days of symptom onset and had no requirement for supplemental oxygen (room air saturations <93%).
- Median age was 39-46 years; only 10-15% of the participants were over age 65.
- Majority of participants were white (88-95%) and 37-48% were Hispanic.
- 577 participants were randomized to receive 700 mg bamlanivimab (n=101), 2,800 mg bamlanivimab (n=107), 7,000 mg bamlanivimab (n=101), 2,800 mg bamlanivimab combined with 2,800 mg etesevimab (n=112) or placebo (n= 156).
- 82% of the population was receiving corticosteroids at the time of randomization.
- Change in SARS-CoV-2 log viral load at day 11.
- Change in SARS-CoV-2 log viral load at day 11 was significant when compared to placebo for only the combination group, which had a log viral load drop of -0.57 (95% CI, -1.0 to -0.14).
- Hospitalization or emergency room visit occurred in 5.8% of the placebo recipients, as compared with 1% of the 700 mg bamlanivimab group, 1.9% of the 2,800 mg bamlanivimab group, 2% of the 7,000 mg bamlanivimab group and 0.9% of the combination treatment group.
- The bamlanivimab 700 mg group and the combination group had statistically significant differences in change in mean symptom score from baseline when compared to the placebo group.
- However, there was no significant difference among the two higher dose bamlanivimab monotherapy groups, arguing against a dose-response relationship.
- Post hoc analyses among older (>65 years) and obese individuals showed slightly lower hospitalization rates among those who received bamlanivimab 700 mg or combination treatment.
- Treatment-emergent bamlanivimab resistance was seen in 1% of the combination group, as compared to 7.1% of the 700 mg bamlanivimab group, 9.8% of the 2,800 mg bamlanivimab group and 11.3% of the 7,000 mg bamlanivimab group.
- Treatment-emergent adverse event rates in the various treatment groups were not different from those observed in placebo groups.
- This was a small study, with low numbers in all treatment groups, so it would be difficult to pick up a somewhat infrequent safety event or somewhat small treatment effect.
- Study participants were relatively young and relatively healthy and may not represent the people at highest risk for progression to more severe disease.
- It is unclear whether the correct doses for the combination treatment were selected, and if other doses might have had more impact on viral load.
- It is unclear how viral load correlates with clinical course, and likewise unclear what impact on clinical status the lowering of SARS-CoV-2 viral load might have. Of note, viral load decreases with natural infection and no (or placebo) intervention, as part of immune clearance.
- It is possible that an earlier time point than 11 days would have showed a difference in primary outcome.
REGEN-COV, a Neutralizing Antibody Cocktail, in Outpatients with COVID-19 (Weinrich, January 2021).
Overall, in this interim analysis of Phase 1–3 trials of 275 symptomatic outpatients with confirmed SARS-CoV-2 infection, the REGEN-COV antibody cocktail reduced viral load, with a greater effect in patients whose immune response had not yet been initiated or who had a high viral load at baseline. Safety outcomes were similar in the combined REGEN-COV dose groups and the placebo group.
- Interim results from phase 1–3 trials of 275 symptomatic outpatients with confirmed SARS-CoV-2 infection.
- Patients were randomly assigned (1:1:1) to receive placebo, 2.4 g of REGEN-COV or 8.0 g of REGEN-COV and were prospectively characterized at baseline for endogenous immune response against SARS-CoV-2 (serum antibody–positive or serum antibody–negative).
- Among the 275 patients, 90 were assigned to receive high-dose REGEN-COV, 92 to receive low-dose REGEN-COV and 93 to receive placebo.
- The median age was 44.0 years, 49% were male, 13% identified as Black or African American and 56% identified as Hispanic or Latinx.
- The median number of days of reported COVID-19–related symptoms before randomization was 3.0.
- At randomization, 30 of 275 patients (11%) tested negative for SARS-CoV-2 by qualitative RT-PCR and 17 of 275 (6%) tested positive for SARS-CoV-2 but did not have baseline viral load data; therefore, 228 of the 275 patients (83%) who underwent randomization made up the modified full analysis set (i.e., those patients who were confirmed SARS-CoV-2–positive by RT-PCR at baseline).
- At baseline, 123 patients (45%) were serum antibody–positive, 113 (41%) were serum antibody–negative and 39 (14%) had unknown antibody status.
- Time-weighted average change from baseline in viral load from day 1 through day 7 and the percentage of patients with at least one COVID-19–related medically attended visit through day 29.
- The least-squares mean difference (combined REGEN-COV dose groups vs. placebo group) in the time-weighted average change in viral load from day 1 through day 7 was −0.56 log10 copies per milliliter (95% CI, −1.02 to −0.11) among patients who were serum antibody–negative at baseline and −0.41 log10 copies per milliliter (95% CI, −0.71 to −0.10) in the overall trial population.
- In the overall trial population, 6% of the patients in the placebo group and 3% of the patients in the combined REGEN-COV dose groups reported at least one medically attended visit; among patients who were serum antibody–negative at baseline, the corresponding percentages were 15% and 6% (difference, −9 percentage points; 95% CI, −29 to 11).
- Both REGEN-COV doses (2.4 g and 8.0 g) were associated with few and mainly low-grade toxic effects. An adverse event of special interest was reported in 2 of 93 patients (2%) in the placebo group and in 2 of 176 patients (1%) in the combined REGEN-COV dose groups.
- Interim analysis with small patient sample.
- The median age of the patient population was young (44 years); may not be generalizable to an older patient population.
- Patients’ COVID-19 severity status was not provided.
SARS-CoV-2 Neutralizing Antibody Bamlanivimab in Outpatients with COVID-19 (Chen, January 2021).
Overall, in this interim analysis, in those that received bamlanivimab, the viral load at day 11 was lower than that in the placebo group only among those who received the 2,800-mg dose. However, a decreased viral load at day 11 did not appear to be a clinically meaningful endpoint.
- Interim analysis of phase 2 trial of 452 outpatients who were recently diagnosed with mild or moderate COVID-19 and randomly assigned to receive a single intravenous infusion of neutralizing antibody bamlanivimab (N=309) in one of three doses (700 mg, N=101; 2,800 mg, N=107; or 7,000 mg, N=101) or placebo (N=143).
- This preplanned interim analysis was triggered on Sept. 5, 2020, when the last patient who was randomly assigned to receive bamlanivimab reached day 11.
- The two groups were well-balanced regarding risk factors at the time of enrollment. Nearly 70% of patients had at least 1 risk factor for severe COVID-19: age >65 years, BMI >35 kg/m2 or at least one relevant coexisting illness.
- Patients received an infusion of bamlanivimab or placebo within a median of 4 days after the onset of symptoms; at the time of randomization, >80% of the patients had only mild symptoms.
- The observed mean PCR cycle threshold value of 23.9 on the day of infusion equated to that a recently diagnosed population would have with a high viral burden.
- Change from baseline in the SARS-CoV-2 viral load at day 11 (±4 days) after positive results on testing.
- Data regarding virologic features and symptoms were collected up to day 29 in this trial.
- By day 11, the majority of patients had a significant trend toward viral clearance, including those in the placebo group.
- The observed mean decrease from baseline in the log viral load for the entire cohort was −3.81 (baseline mean, 6.36; day 11 mean, 2.56), corresponding to a decrease by more than a factor of 4,300 in the SARS-CoV-2 burden, for an elimination of more than 99.97% of viral RNA. For patients who received the 2,800-mg dose of bamlanivimab, the difference from placebo in the decrease from baseline was −0.53 (95% CI, −0.98 to −0.08; p=0.02), for a lower viral load by a factor of 3.4. However, smaller differences from placebo in the decrease from baseline were observed among the patients who received the 700-mg dose (−0.20; 95% CI, −0.66 to 0.25; p=0.38) and the 7,000-mg dose (0.09; 95% CI, −0.37 to 0.55; p=0.70).
- On days 2 to 6, those who received bamlanivimab had a slightly lower severity of symptoms than those who received placebo.
- The percentage of patients who had a COVID-19–related hospitalization or visit to an emergency department was 1.6% in the bamlanivimab group and 6.3% in the placebo group.
- The percentage of patients who had an adverse event during treatment was 22.3% (69 of 309) in the bamlanivimab group and 24.5% (35 of 143) in the placebo group.
- The primary endpoint of decreased viral load at day 11 was not a clinically meaningful endpoint as the viral load was significantly decreased from baseline for a majority of patients.
- Patients with severe COVID-19 were not included in this study; applicability of findings may only apply to those with mild/moderate COVID-19.
A Neutralizing Monoclonal Antibody for Hospitalized Patients with COVID-19 (ACTIV-3/TICO Bamlanivimab Study Group, December 2020). Sustained recovery over 90 days was assessed in hospitalized patients with COVID-19 without end-organ failure randomized to receive either bamlanivimab (7,000 mg) or placebo. All patients received supportive care as background therapy, including remdesivir and, when indicated, supplemental oxygen and glucocorticoids. In October 2020, the data and safety monitoring board recommended stopping enrollment for futility after 314 patients (163 in the bamlanivimab group and 151 in the placebo group) had undergone randomization and infusion. Across the 7 categories, the odds ratio of being in a more favorable category in the bamlanivimab group than in the placebo group was 0.85 (95% CI, 0.56 to 1.29; p=0.45). The percentage of patients with the primary safety outcome (a composite of death, serious adverse events or clinical grade 3 or 4 adverse events through day 5) was similar in the bamlanivimab group and the placebo group (19% and 14%, respectively; OR, 1.56; 95% CI, 0.78 to 3.10; p=0.20).