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Monoclonal Antibodies

Last updated: February 17, 2021

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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 utilizing mice genetically modified to have an immune system (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 monoclonal antibody products under development for SARS-CoV-2 target the spike protein, which the virus utilizes to enter host cells (Marovich, June 2020).

Products farthest along in clinical trials have been created by Eli Lilly and Regeneron. Eli Lilly’s monoclonal antibody regimen, bamlanivimab (also known as LY-CoV555), consists of two antibodies directed against the SARS-CoV-2 spike protein and its receptor binding domain; Regeneron’s products, casirivimab (REGN10933) and imdevimab (REGN10987), consists of two antibodies that bind to different regions of the SARS-CoV-2 spike protein receptor binding domain.   

In November 2020 the 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 two outpatient phase 2 randomized controlled trials which showed a reduction in COVID-19 related hospitalization or emergency room visits

In February 2021, the FDA granted emergency use authorization for the combination of bamlanivimab and etesevimab for the treatment of mild to moderate COVID-19 in patients who are at high risk for progressing to severe disease. The approval was based on an interim analysis of the BLAZE-1 clinical trial announced via press release but not yet published. 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. 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).  

Outpatient trials in progress 

To date, there are three published studies on the use of monoclonal antibodies to treat COVID-19 in the outpatient setting: twointerim analyses of BLAZE-1, one of which examined the use of bamlanivimab in outpatients (Chen, October 2020) and one of which examined the use of the combination of bamlanivimab and etesevimab (Gottlieb, January 2021); and an interim analysis of a double-blind, phase 1–3 trial data of REGN-COV2 (Weinreich, December 2020). Other outpatient trials examining the use of LY-CoV555 are ongoing.    

Inpatient trials in progress 

ACTIV-3 is an NIH-sponsored inpatient phase 3 clinical trial comparing bamlanivimab and remdesivir against placebo and remdesivir. In October 2020, the trial's independent data safety monitoring board recommended pausing the study after noting the group of patients who received five days of LY-CoV555 had a different clinical status than the group who had received placebo and subsequently halted enrollment after determining a lack of efficacy. Other LY-CoV555 trials continue, and further data is forthcoming. 

REGN-COV2, developed by Regeneron, consists of two antibodies that bind to different regions of the SARS-CoV-2 spike protein receptor binding domain. In October 2020, an independent data monitoring committee recommended halting a study examining the use of REGN-CoV in hospitalized patients requiring high-flow oxygen or mechanical ventilation, due to a potential safety signal and an unfavorable risk/benefit profile. Other cohorts continue to enroll. Regeneron also has ongoing trials examining the use of its product in outpatients with COVID-19; current data is only available via press release

A review of the literature on this topic will be developed once relevant clinical data in humans are made fully available to the public.

Guidelines

IDSA guidelines recommend against the routine use of bamlanivimab in ambulatory and hospitalized patients, and casirivimab/imdevimab in ambulatory patients with COVID-19.  

  • The guidelines note that in patients at increased risk, bamlanivimab is a reasonable treatment option if, after informed decision-making, the patient puts a high value on the uncertain benefits and a low value on uncertain adverse events. 
  • The FDA 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 chartsOR 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.   

NIH guidelines state there are insufficient data to recommend either for or against the use of bamlanivimab for the treatment of outpatients with mild to moderate COVID-19. They also state: 

  • Bamlanivimab should not be considered the standard of care for the treatment of patients with COVID-19.  
  • Health care providers are encouraged to discuss participation in bamlanivimab clinical trials with their patients.  
  • Patients who are hospitalized for COVID-19 should not receive bamlanivimab outside of a clinical trial.  

Key Literature

REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with COVID-19 (Weinreich, December 2020). 

Patient population: 

  • 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 REGN-COV2, or 8.0 g of REGN-COV2 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 REGN-COV2, 92 to receive low-dose REGN-COV2, 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 Latino. 
  • 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.  

Primary endpoint: 

  • 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. 

Key findings: 

  • The least-squares mean difference (combined REGN-COV2 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 REGN-COV2 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 REGN-COV2 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 REGN-COV2 dose groups. 

Limitations: 

  • 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. 

Overall, in this interim analysis of phase 1–3 trials of 275 symptomatic outpatients with confirmed SARS-CoV-2 infection, the REGN-COV2 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 REGN-COV2 dose groups and the placebo group. 
 

SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with COVID-19 (Chen, October 2020). 

Patient population: 

  • 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 LY-CoV555 (N=309) in one of three doses (700 mg (N=101), 2800 mg (N=107), or 7000 mg (N=101) or placebo (N=143). 
    • This preplanned interim analysis was triggered on September 5, 2020, when the last patient who was randomly assigned to receive LY-CoV555 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 of age, body-mass index (BMI) > 35 kg/m2, or at least one relevant coexisting illness 
  • Patients received an infusion of LY-CoV555 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 (Ct) value of 23.9 on the day of infusion equated to that of which a recently diagnosed population would have with a high viral burden.  

Primary endpoint: 

  • 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. 

Key findings: 

  • 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 4300 in the SARS-CoV-2 burden, for an elimination of more than 99.97% of viral RNA. For patients who received the 2800-mg dose of LY-CoV555, the difference from placebo in the decrease from baseline was −0.53 (95% confidence interval [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 7000-mg dose (0.09; 95% CI, −0.37 to 0.55; P=0.70). 
  • On days 2 to 6, those who received LY-CoV555 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 LY-CoV555 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 LY-CoV555 group and 24.5% (35 of 143) in the placebo group.  

Limitations: 

  • 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. 

Overall, in this interim analysis, in those that received LY-CoV555, the viral load at day 11 was lower than that in the placebo group only among those who received the 2800-mg dose. However, a decreased viral load at day 11 did not appear to be a clinically meaningful endpoint. 

 

Additional Literature

A Neutralizing Monoclonal Antibody for Hospitalized Patients with COVID-19 (ACTIV-3/TICO Ly-CoV555 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 LY-CoV555 (7000 mg) or placebo. All patients received supportive care as background therapy, including remdesivir and, when indicated, supplemental oxygen and glucocorticoids. On October 26, 2020, the data and safety monitoring board recommended stopping enrollment for futility after 314 patients (163 in the LY-CoV555 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 LY-CoV555 group than in the placebo group was 0.85 (95% confidence interval [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 LY-CoV555 group and the placebo group (19% and 14%, respectively; odds ratio, 1.56; 95% CI, 0.78 to 3.10; P=0.20). 

 

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