The COVID-19 pandemic continues to rage unabated in many parts of the world. India is by far the worst affected, with uncontrolled transmission across the country. Mutant variants have been implicated in the second wave that has ravaged most of the states. The quest for therapeutic options continues; monoclonal antibodies have been the focus of interest, particularly as a therapeutic option in mild to moderate disease, with the potential to prevent progression to severe disease. Monoclonal antibody therapy received widespread attention in the mainstream and social media when it was used to treat COVID-19 infection in the former president of the US. How do monoclonal antibodies work, and what is the evidence so far regarding their efficacy in COVID-19?
Viral entry into cells
The genome of the SARS-CoV-2 virus includes the spike, envelope, membrane, and nucleocapsid proteins. The spike protein consists of the S1 and S2 subunits. The receptor-binding domain of the S1 subunit attaches to the ACE-2 receptor on the host cell. The S1 to ACE-2 receptor attachment triggers a conformational change in the S2 subunit leading to fusion between the virus and the host cell, enabling entry of the virus into the cell.
The host immune response
The host immune system generates antibodies to the virus as a defense mechanism. COVID-19 infection results in the production of neutralizing antibodies after about 10 days of disease onset; higher antibody levels are associated with more severe disease. Antibody therapy using convalescent plasma had shown initial promise in the treatment of COVID-19; however, randomized controlled trials have repeatedly failed to demonstrate improvement in clinical endpoints.1,2 This may be due to the variability in the concentration of neutralizing antibodies in the donor plasma and failure to provide a standardized dose. Vaccines generate an antibody response too; however, they are ineffective once the infection has already occurred.
How do monoclonal antibodies work in COVID-19?
Monoclonal antibodies are identical immunoglobulins derived from a single clone of B-lymphocytes. The receptor-binding domain of the S1 unit of the spike protein plays the most critical role in viral entry into the cell. The relative accessibility of the receptor-binding domain makes it a readily available target for monoclonal antibody therapy. Monoclonal antibodies may reduce viral load, alleviate symptoms, and reduce the requirement for hospitalization. Several monoclonal antibodies are being evaluated in COVID-19 that target the spike protein of the SARS-COV-2 virus.
What is the evidence?
Monoclonal antibodies are currently being evaluated in the outpatient treatment of ambulatory patients with mild to moderate COVID-19. Efficacy data are available for bamlanivimab alone and in combination with etesevimab, and the casirivimab-imdevimab combination.
Bamlanivimab
The BLAZE-1 phase II trial randomized 452 patients with mild to moderate illness to a single intravenous infusion of bamlanivimab 700 mg, 2800 mg, or 7000 mg compared to a placebo group. The primary outcome was the difference in the viral load on day 11 compared to baseline. A significant reduction in the viral load was observed with the 2800 mg dose alone.3 The lack of benefit of the higher dose may be attributable to a prozone effect – wherein a higher dose of antibody may reduce the ability to form immune complexes.4 The requirement for hospitalization was lower among patients who received bamlanivimab compared to placebo (1.6 vs 6.3%). Symptom severity was lower from days 2–6 among patients who received bamlanivimab.
Bamlanivimab-etesevimab combination
The emergence of different variants of the virus with increased infectivity and a more severe clinical course has been of growing concern. Newer variants may also become resistant to monoclonal antibody therapy. Hence, there is increased focus on the use of a combination of two monoclonal antibodies aimed to reduce the possibility of lack of effectiveness due to variant strains of the virus.
The BLAZE-1 study also evaluated bamlanivimab monotherapy and in combination with etesevimab compared to placebo among ambulatory patients with mild to moderate COVID-19 in the latter phase of the trial.5 The combination treatment included 2800 mg each of bamlanivimab and etesevimab. This cocktail was administered to 112 patients and compared with 156 patients who received placebo. In this study, the bamlanivimab-etesevimab combination was associated with a statistically significant decrease in the viral load on day 11 compared to placebo; the bamlanivimab monotherapy did not show a significant reduction in the viral load. The combination therapy also significantly reduced the requirement for hospitalization compared to placebo (2.1% vs. 7.0%; risk reduction: 70%; p = 0.0004). This trial led to emergency use approval of the cocktail by the FDA in the US for the treatment of mild to moderate COVID-19 infection in patients more than 12 years old with an increased risk of progression to severe disease. The European Medical Agency (EMA) has also recommended the use of this cocktail in COVID-19 patients who are not on supplemental oxygen, with a high risk of progression to severe disease.
Casirivimab-imdevimab combination
This monoclonal antibody cocktail binds to non-overlapping sections of the receptor-binding domain of the SARS-CoV-2 virus.6 The casirivimab-imdevimab combination is being evaluated among ambulatory patients in a multinational phase 1/2/3 trial. The phase 3 study compared the efficacy 1200 mg and 2400 mg of the cocktail with placebo among 4567 patients more than 12 years old with mild to moderate disease, who were at risk of developing severe disease. The preliminary report revealed a significant reduction in the requirement for hospitalization by 70% in patients who received 1200 mg and by 71% among those who received 2400 mg, compared with placebo. Besides, a significant 4-day reduction in the median duration of symptoms (from 14 to 10 days) was observed with both doses.7 Data on viral clearance have not yet been reported from this trial. However, a previous report with interim data in the phase 1/2 segment of the study demonstrated a significant reduction in the time-weighted average change in viral load with this combination compared to baseline. A more profound effect was noted in patients in whom an immune response had not yet been evoked following infection and those with a high viral load at baseline.
The FDA has provided emergency use authorization for casirivimab-imdevimab in mild to moderate COVID-19 among patients 12 years of age or older, with a bodyweight of >40 kg and are at high risk for progression to severe disease.8 The European Medicines supported casirivimab-imdevimab as a therapeutic option in COVID-19 patients who do not require supplemental oxygen and are at high risk of progression to severe COVID-19.9 The Central Drugs Standards Control Organisation (CDSCO) in India has also provided emergency use authorisation (EUA) for the casirivimab-imdevimab cocktail in India.10 This combination is also currently being investigated in the phase III open-label RECOVERY trial among hospitalized patients in the UK.
Monoclonal antibodies as prophylaxis against COVID-19
Among unvaccinated individuals and those who do not evoke an appropriate antibody response to vaccines, monoclonal antibodies may offer short-term protection. Several monoclonal antibodies are currently under investigation for the prevention of infection, especially against strains that are not adequately protected by vaccines.11 Besides, monoclonal antibodies may have a possible role in post-exposure prophylaxis among individuals at high risk of severe disease.
Subcutaneous and intranasal administration
The subcutaneous administration of casirivimab-imdevimab has been investigated. Household contacts who were exposed SARS-CoV-2 demonstrated 72% protection against symptomatic infection during the first week and by 93% subsequently. Hence, subcutaneous administration of monoclonal antibodies may play a complementary role along with vaccines in the prevention of severe COVID-19 infection.12
Intranasal administration of monoclonal antibodies is convenient to use. An early study with intranasal foralumab, an anti-CD3 human monoclonal antibody, revealed more rapid improvement in CT infiltrates either alone or in combination with dexamethasone compared to a control group.13
Summary
- Several monoclonal antibodies directed against the receptor-binding domain of the SARS-CoV-2 virus are currently undergoing clinical evaluation
- The potential therapeutic benefit from monoclonal antibodies emanate from their antiviral effect during the early stage of the disease
- If administered during the stage of viral replication, they may prevent progression to severe disease, particularly in individuals who are at high risk
- The emergence of variant strains may result in lack of efficacy; hence, combination therapy is considered more appropriate
- Continued surveillance of circulating strains to identify mutations is necessary to ensure efficacy with monoclonal antibody therapy
- Currently recommended monoclonal antibody cocktails include the bamlanivimab-etesevimab and the casirivimab-imdevimab combination; both combinations have been shown to reduce progression to severe illness in non-hospitalized patients
References
1. Simonovich VA, Burgos Pratx LD, Scibona P, et al. A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia. N Engl J Med. 2021;384(7):619-629. doi:10.1056/NEJMoa2031304
2. Agarwal A, Mukherjee A, Kumar G, Chatterjee P, Bhatnagar T, Malhotra P. Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial). BMJ. Published online October 22, 2020:m3939. doi:10.1136/bmj.m3939
3. Chen P, Nirula A, Heller B, et al. 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
4. Neutralizing Antibody LY-CoV555 for Outpatient Covid-19. N Engl J Med. 2020;384(2):189-189. doi:10.1056/NEJMc2033787
5. 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. doi:10.1001/jama.2021.0202
6. Hurt AC, Wheatley AK. Neutralizing Antibody Therapeutics for COVID-19. Viruses. 2021;13(4):628. doi:10.3390/v13040628
7. New phase III data shows investigational antibody cocktail casirivimab and imdevimab reduced hospitalisation or death by 70% in non-hospitalised patients with COVID-19. Accessed May 8, 2021. https://www.roche.com/investors/updates/inv-update-2021-03-23.htm
8. Commissioner O of the. Coronavirus (COVID-19) Update: FDA Authorizes Monoclonal Antibodies for Treatment of COVID-19. FDA. Published November 23, 2020. Accessed May 8, 2021. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-monoclonal-antibodies-treatment-covid-19
9. EMA issues advice on casirivimab and imdevimab antibody cocktail for the treatment of mild-to-moderate COVID-19. Accessed May 8, 2021. https://www.roche.com/media/releases/med-cor-2021-02-26b.htm
10. Roche receives Emergency Use Authorisation in India for its investigational Antibody Cocktail (Casirivimab and Imdevimab) used in the treatment of Covid-19 | Cipla. Accessed May 8, 2021. https://www.cipla.com/press-releases-statements/roche-receives-EUA-India-investigational-antibody-cocktail-casirivimab-Imdevimab-covid
11. Lilly’s neutralizing antibody bamlanivimab (LY-CoV555) prevented COVID-19 at nursing homes in the BLAZE-2 trial, reducing risk by up to 80 percent for residents | Eli Lilly and Company. Accessed May 8, 2021. https://investor.lilly.com/news-releases/news-release-details/lillys-neutralizing-antibody-bamlanivimab-ly-cov555-prevented
12. Phase 3 Prevention Trial Showed 81% Reduced Risk of Symptomatic SARS-CoV-2 Infections with Subcutaneous Administration of REGEN-COVTM (casirivimab with imdevimab) | Regeneron Pharmaceuticals Inc. Accessed May 8, 2021. https://investor.regeneron.com/news-releases/news-release-details/phase-3-prevention-trial-showed-81-reduced-risk-symptomatic-sars/
13. Tiziana posts clinical COVID-19 data on nasal antibody delivery. FiercePharma. Accessed May 8, 2021. https://www.fiercepharma.com/drug-delivery/tiziana-posts-clinical-covid-19-data-nasal-antibody-delivery
