T he role of monoclonal antibody drugs in the prevention of COVID-19 infection and their role in the treatment of patients with complicated forms of the infectious disease: a literature review

Actuality

The consequences of the coronavirus disease (COVID-19) pandemic have severely impacted public health and healthcare systems worldwide and have led to significant changes in strategies, treatment approaches, and prevention of viral diseases. As of the end of March 2022, when a substantial decline in morbidity was observed, according to World Health Organization statistics, 500,269,744 cases of infection and 6,192,488 deaths from COVID-19 had been registered worldwide [1].

The global spread of the disease in many regions of the world initiated the development and improvement of immunological prevention and treatment methods for this pathology and the creation of a number of effective antiviral vaccines [2, 3]. The increase in morbidity during the pandemic stimulated research in several scientific centers to develop new treatment methods, including the administration of antibodies with convalescent plasma, and facilitated the development of new technologies to produce large quantities of monoclonal antibodies neutralizing the severe acute respiratory syndrome coronavirus (SARS-CoV-2). Within a short period at the height of the epidemic, six monoclonal antibodies were developed and received Emergency Use Authorization (EUA) from drug regulatory agencies in the United States and South Korea [4, 5].

The creation of new effective immune therapy agents to mitigate the consequences of the COVID-19 pandemic was an urgent global need in all countries. Numerous studies have established that neutralizing antibodies are effective antiviral agents because they can be rapidly used to prevent disease progression and can accelerate patient recovery without the need for a fully developed host immune response (Tuccori M et al., 2020; Kumar S et al., 2021) [6, 7].

According to several scientific publications, monoclonal antibody (mAb) drugs have revolutionized the treatment of various human diseases, including cancer, autoimmune and inflammatory conditions. Their widespread use in medical pharmacotherapy represents a new stage in the treatment of infectious diseases. Over the past decade, innovative immunological methods have made it possible to rapidly isolate antibodies from recovering subjects, humanized animals, or in vitro‑assembled libraries, and have proven that mAbs can be effective against new highly virulent pathogens and their mutant forms. During the five years since the beginning of the COVID-19 epidemic, a very large number of mAbs have been developed to combat COVID-19 [8].

Monoclonal antibody therapy opens up significant prospects for the prevention and treatment of COVID-19. As early as March 2020, in the region of the initial outbreak of this viral infection and in the United States, the Chinese Antibody Society was established to coordinate immunological protection of the population from the threat of COVID-19 spread, and in cooperation with the Antibody Society, it initiated the "COVID-19 Antibody Therapeutics Tracker" ("Tracker") program to track antibody‑based interventions in preclinical and clinical scientific developments worldwide (Chinese Antibody Society, Cambridge, MA, USA). The American Antibody Society (Framingham, MA), the National Cancer Institute, and the National Institutes of Health (Bethesda, MD, USA) actively participated in the work of the society and the creation of new mAbs [9].

A new database named CoV-AbDab, created in Europe by members of the Oxford Protein Informatics Group and experts from the Department of Statistics at the University of Oxford (United Kingdom), contained data on more than 1,400 published or patented antibodies and nanobodies binding to at least one betacoronavirus, being the first library of antibodies binding to both SARS-CoV-2 and other betacoronaviruses such as SARS-CoV-1 and MERS-CoV (Raybould MIJ et al., 2021) [10]. Experts from these organizations and structures determined that most protein compounds among the antibody candidates against SARS-CoV-2 appear to target the viral spike (S) protein, and many of them are full‑size monoclonal antibodies (Yang L et al., 2020) [11]. Among the antibodies blocking the SARS‑CoV‑2 S protein, clinical trial data were included for mAbs LY‑CoV555, REGN‑COV2, JS016, TY027, CT‑P59, BRII‑196, BRII‑198, and SCTA01. It was assumed that clinical evaluations and trials of neutralizing SARS‑CoV‑2 antibodies would help determine the utility of these antibodies as a new class of therapeutic agents for the treatment of COVID‑19 and anticipated coronavirus infections [11].

By August 2020, the Coronavirus Antiviral Research Database (CoV‑RDB; covdb.stanford.edu) in the United States contained data on more than 2,800 cell culture experiments, entry assays, and biochemical experiments, as well as over 250 animal model studies and 70 clinical trials from more than 400 published articles. This body of scientific information consisted of more than 80% data on SARS‑CoV‑2, SARS‑CoV, and MERS‑CoV. According to data from the Division of Infectious Diseases at Stanford University School of Medicine (Stanford, CA, USA), approximately 75% of experiments used new compounds, including monoclonal antibodies and receptor‑binding inhibitors, viral protease inhibitors, host‑targeting inhibitors, polymerase inhibitors, interferons, fusion inhibitors, and animal or human cell protease inhibitors. Among more than 970 compounds with established or presumed mechanisms of action, over 14% were licensed in the United States for other indications, and in 60% of cases these were preclinical investigational drugs or compounds [12, 13].

The search for antibodies blocking the SARS‑CoV‑2 S protein included data from a number of clinical trials characterizing mAb preparations LY‑CoV555, REGN‑COV2, JS016, TY027, CT‑P59, BRII‑196, BRII‑198, and SCTA01. It was assumed that clinical trials of these neutralizing SARS‑CoV‑2 antibodies would help determine their utility as a new class of therapeutic agents for the treatment of COVID‑19 and anticipated, including mutating, coronavirus infections [11]. During this period, the use of various virus‑neutralizing antibodies for the treatment of coronavirus infection was approved by the US Food and Drug Administration (FDA) in 2020–2021 [4, 5].

Immunological and biochemical basis and prerequisites for the development of monoclonal antibody drugs and their use for the prevention and treatment of patients with COVID‑19.

According to studies conducted by specialists in biochemistry, immunology, virology, pharmacology, and public health, human monoclonal antibodies (mAbs) neutralizing severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) and its variants represent a promising opportunity for prevention of viral infection and disease, as well as for the treatment of established disease and the elimination of post‑COVID organ changes in recovered individuals [7]. Most human monoclonal antibodies (mAbs) neutralizing SARS‑CoV‑2 recognize the receptor‑binding domain of the spike (S) protein and block the interaction of the virus with the cellular angiotensin‑converting enzyme 2 receptor, an angiotensin II type G‑protein coupled receptor (GPCR) (Suryadevara N et al., 2021) [14]. The spike (S) protein of SARS‑CoV‑2 can be the main target of neutralizing antibodies (NAbs). They are mostly targeted either at the receptor‑binding domain (RBD) or at the N‑terminal domain (NTD) of the spike glycoprotein [10, 12].

According to a meta‑analysis by British authors from the University of Oxford (Oxford Protein Informatics Group), out of 1,400 antibodies and nanobodies against coronavirus, 1,130 bind to SARS‑CoV‑2 through these structures (Raybould MIJ et al., 2021) [10]. American immunologists from the Division of Biology and Biological Engineering at the California Institute of Technology (Pasadena, CA, USA), Barnes CO et al. (2020), classify RBD‑specific NAbs into four main classes (I, II, III, and IV) [8, 15, 16]. Class I and II NAb antibodies interact with the angiotensin‑converting enzyme 2 (ACE2) binding region or the receptor‑binding motif (RBM) of the RBD on the spike glycoprotein [15]. Structural comparisons allowed researchers to classify antibodies into the following categories: neutralizing antibodies encoded by the VH3–53 gene segment with short CDRH3 loops that block ACE2 and bind only to "up" RBDs [12]; neutralizing antibodies that block ACE2, bind to both "up" and "down" RBDs, and can bind to adjacent RBDs [15]; neutralizing antibodies that bind outside the ACE2 site and recognize both up and down RBDs; and previously described antibodies that do not block ACE2 and bind only to down RBDs [16]. The RBM region is responsible for primary contact with the host ACE2 receptor to initiate viral entry [17]. Class IV antibodies, dependent on the core region I, exhibit broad neutralizing activity against SARS‑CoV‑2, its variants, and other related coronaviruses [10, 12, 15, 18]. More recently, NAbs targeting new epitopes on the S2 domain (stalk helix region) of the spike have been identified that possess broad neutralizing activity, i.e., they neutralize SARS‑related and other human coronaviruses (hCoV) [19–22]. Staff of the Department of Immunology and Microbiology at the Scripps Research Institute (California, USA) presented evidence of pre‑existing cross‑reactive serum antibodies to SARS‑CoV‑2 in pre‑pandemic donors and the presence of pre‑existing cross‑reactive memory B cells that are activated during SARS‑CoV‑2 infection. According to their data, monoclonal antibodies have varying degrees of cross‑reactivity with betacoronaviruses, including SARS‑CoV‑1 and endemic coronaviruses [19–22].

Immunological studies have established that most human monoclonal antibodies (mAbs) neutralizing SARS‑CoV‑2 recognize the receptor‑binding domain of the spike (S) protein and block virus interaction with the cellular angiotensin‑converting enzyme 2 receptor [14]. Analyzing a panel of human mAbs binding to various epitopes on the N‑terminal domain (NTD) of the S protein obtained from convalescent SARS‑CoV‑2 donors, researchers from the Vaccine Research Center and Vanderbilt University Medical Center (Nashville, TN, USA) found that a minority of them possess neutralizing activity. Only two mAbs (COV2‑2676 and COV2‑2489) inhibited infection by authentic SARS‑CoV‑2 viruses and recombinant VSV/SARS‑CoV‑2 viruses. The authors mapped their binding epitopes using alanine scanning mutagenesis and selection of functional neutralization‑escape variants of the SARS‑CoV‑2 S protein. The study showed that these antibodies neutralize partially by inhibiting a post‑attachment step in the infection cycle, COV2‑2676 and COV2‑2489, providing potential for both prophylaxis and therapy, and that Fc effector functions were required for optimal protection. The researchers concluded that viral infection induces the synthesis of potent NTD‑specific monoclonal antibodies that use neutralizing and Fc‑mediated activity to protect against SARS‑CoV‑2 infection [14].

Based on the findings, several neutralizing monoclonal antibodies (mAbs) against SARS‑CoV‑2 have been developed and recognized as effective in preventing COVID‑19, and the US FDA issued emergency use authorizations for their neutralization in outpatient, non‑hospitalized patients with mild to moderate COVID‑19 [4, 5].

The literature pays considerable attention to the possibility of replacing antiviral therapy with neutralizing monoclonal antibodies, where dosing to ensure proper neutralizing capacity of antibodies can be more precise. In an analytical review by English authors from the Botnar Research Centre (University of Oxford, Oxford, UK), Taylor PC et al. (2021), it was noted that the large‑scale production of recombinant monoclonal antibodies has already become fully adequate to meet demand and competitive in efficacy and cost with other treatment methods. The use of neutralizing monoclonal antibodies can overcome the limitations characteristic of convalescent plasma therapy (CPT) (including reducing the risk of blood‑borne diseases, decreasing the time required for the production of high‑affinity antibodies, and the risk of insufficient antibody production). In addition, the high titer of neutralizing antibodies necessary for sufficient efficacy of donor plasma therapy is inherent in neutralizing monoclonal antibodies. Researchers and experts believe that there is a need for effective implementation into clinical practice, including the use of neutralizing mAbs and convalescent plasma for the treatment of SARS‑CoV‑2 [23].

Modern immunological data, based on compiled universal libraries of mAbs obtained from healthy human donors, have the advantage that antibodies can be generated quickly, independent of the availability of material from convalescent patients during a pandemic. Staff at the Braunschweig Institute of Biochemistry, Biotechnology and Bioinformatics (Germany) presented data on the use of phage display to select anti‑spike antibodies against SARS‑CoV‑2 from native human antibody gene libraries HAL9/10 and subsequent identification of more than 300 unique fully human antibodies against S1. They found that 17 antibodies bind to RBD, demonstrating inhibition of spike binding to ACE2‑expressing cells as scFv‑Fc, and neutralize active SARS‑CoV‑2 infection of VeroE6 cells. The researchers showed that antibody STE73‑2E9 has the property of neutralizing active SARS‑CoV‑2 as IgG and binds to the ACE2‑RBD interface in vitro [24].

Chinese authors from the CAS Key Laboratory of Microbial Physiological and Metabolic Engineering, Institute of Microbiology, Chinese Academy of Sciences (Beijing, China) reported the isolation of two specific human monoclonal antibodies (designated CA1 and CB6) from a patient recovering from COVID‑19. CA1 and CB6 demonstrated potent, SARS‑CoV‑2‑specific neutralizing activity in vitro. Administration of mAb CB6 inhibited SARS‑CoV‑2 infection in rhesus macaques and was effective when used therapeutically. They performed structural studies showing that CB6 recognizes an epitope that overlaps with the ACE2 binding sites in the SARS‑CoV‑2 RBD, thereby preventing virus‑receptor interaction through both steric hindrance and direct competition for interface residues. The authors believe that mAb CB6 warrants further study as a clinical candidate [25].

High antiviral activity of several mAb preparations was shown in the work of staff from the Virology Section, Division of Infectious Diseases and Immunology, Utrecht University (Utrecht, the Netherlands). In a publication by Wang C et al. as early as 2020, a human monoclonal antibody was reported that neutralizes SARS‑CoV‑2 (and SARS‑CoV) in cell culture [26]. To identify neutralizing SARS‑CoV‑2 antibodies, the researchers assessed ELISA (cross‑)reactivity of antibody‑containing supernatants from a collection of 51 SARS‑S hybridomas obtained from immunized H2L2 transgenic mice that encode chimeric immunoglobulins with human variable heavy and light chains and rat constant regions. Four mAbs out of 50 SARS‑S hybridoma supernatants showed ELISA cross‑reactivity with the SARS2‑S1 subunit, of which one, 47D11, had neutralizing activity against SARS‑S and pseudotyped SARS2‑S VSV infection. The chimeric antibody 47D11 H2L2 was modified by the researchers into a fully human immunoglobulin by cloning the human variable heavy and light chain regions into a human immunoglobulin G1 isotypic backbone. The recombinantly expressed human antibody 47D11 was used for further evaluation. According to the authors, this cloned cross‑neutralizing antibody is tropic for a common epitope of such viruses and may have sufficient potential for the prevention and treatment of COVID‑19 [26].

Su SC et al. (2021) from the Institute of Cellular and Organismic Biology, Academia Sinica (Taipei, Taiwan) reported the generation and characterization of a series of chimeric antibodies against the receptor‑binding domain (RBD) of the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) [27]. Individual synthesized antibodies are capable of exhibiting exceptionally potent neutralizing activity in vitro and in vivo, with the most active ones targeting three distinct non‑overlapping epitopes within the RBD of the spike protein of SARS‑CoV‑2 (the virus that caused the COVID‑19 epidemic), which is located on the S1 subunit of the S protein [27]. Cryo‑electron microscopy analyses of two highly potent antibodies in complex with the SARS‑CoV‑2 spike protein showed that they might be particularly useful when combined into cocktail therapy. The efficacy of this antibody cocktail was confirmed by the researchers in mouse and hamster models infected with SARS‑CoV‑2, as both prophylactic and post‑infection treatment. According to their data, with the emergence of more invasive, mutant variants of SARS‑CoV‑2, antibody cocktail therapy opens up great prospects for disease control and prevention of drug resistance [27].

Thus, the study of the immunological structure of the COVID‑19 virus and data from compiled universal mAb libraries obtained from healthy human donors made it possible to rapidly identify the molecular structures of the receptor‑binding domain of the spike (S) protein and, using them, to obtain antibodies that specifically bind to the cellular angiotensin‑converting enzyme 2 receptor and block the processes of virus interaction with these protein structures in various cells and tissues of experimental animals. The efficacy of these mAbs and antibody cocktails has been confirmed in cellular and organoid models of SARS‑CoV‑2‑infected mice and hamsters, both as prophylactic and post‑infection treatment, but there is a need for clinical evidence of their efficacy and safety for widespread implementation.

Clinical studies evaluating the efficacy of monoclonal antibody (mAb) drugs in outpatients for primary prevention of COVID‑19 infection.

With the advent of innovative technologies in etiotropic therapy for COVID‑19, new perspectives have opened up for the treatment of patients with immunodeficiencies and those at high risk of severe coronavirus infection. The use of various virus‑neutralizing mAbs for the treatment of coronavirus infection was approved by the FDA in 2020–2021 [4, 5].

Bamlanivimab was the first monoclonal antibody authorized for the treatment of COVID‑19 (November 9, 2020) and received EUA for the treatment of mild to moderate COVID‑19 in adults and children aged 12 years (≥40 kg) and older with a positive COVID‑19 test result and who are at high risk for progression to severe COVID‑19 and/or hospitalization [28]. The mAb drug bamlanivimab (LY‑CoV555, LY3819253) is a neutralizing monoclonal antibody targeting the receptor‑binding domain of the spike protein on the surface of SARS‑CoV‑2, and its mechanism of action is based on possible blocking of viral entry into the cell [29]. It has undergone clinical trials as a therapeutic agent against COVID‑19 [28].

In the Russian Federation, temporary authorization for use during the pandemic has been granted for combined mAbs (bamlanivimab/etesevimab, casirivimab/imdevimab, cilgavimab/tixagevimab) and single‑component (sotrovimab, regdanvimab) drugs based on recombinant human IgG1 class monoclonal antibodies with direct antiviral action. All mAbs against SARS‑CoV‑2 are indicated for the treatment of adults and children (over 12 years) with mild to moderate COVID‑19, intended for use in outpatient or hospital‑substituting settings, and are most effective when administered as early as possible [30].

The efficacy of bamlanivimab in outpatients with diagnosed mild to moderate COVID‑19 was evaluated in several randomized placebo‑controlled trials, including the US study BLAZE‑1 conducted by staff of the Department of Medicine, Institute of Lung Diseases, and Cedars‑Sinai Medical Center (Los Angeles, CA, USA) [28]. The researchers hypothesized that virus‑neutralizing monoclonal antibodies would reduce viral load, relieve symptoms, prevent disease progression, reduce respiratory complications, and decrease the need for hospitalization. They randomly assigned over 450 patients with diagnosed mild to moderate COVID‑19 to receive a single intravenous dose of the neutralizing antibody LY‑CoV555 (bamlanivimab) at three doses ranging from 700 to 7000 mg compared to placebo. The study assessed quantitative virological endpoints and clinical outcomes. Results were compared by change in viral load from baseline at day 10. The data obtained indicated a reduction in log viral load of more than 3.5‑fold from baseline, which for the entire patient population corresponded to elimination of more than 99% of viral RNA. Depending on the mAb doses used, smaller differences from baseline were observed in patients receiving the minimum dose of 700 mg, as well as the maximum dose of 7.0 g. The optimal dose for preventing viral infection was found to be 2.8 g. Adverse effects of mAb therapy, deterioration of condition, and need for hospitalization or emergency department visits due to COVID‑19 infection were 1.5% in the treatment group and more than 6.0% in the placebo group. The researchers concluded that one of three doses of bamlanivimab (neutralizing mAb LY‑CoV555) appeared to increase the natural decline in viral load over time, while other doses did not accelerate this effect by day 10 after drug administration [28, 31].

In another fragment of this US study, conducted by staff at Massachusetts General Hospital and Harvard Medical School in Boston, Dougan M et al. (2021), a phase III BLAZE‑1 trial in recently diagnosed outpatients with mild to moderate COVID‑19 at high risk of progression to severe disease, the efficacy of a single intravenous infusion of bamlanivimab 2800 mg and etesevimab 2800 mg (administered together) versus placebo within 3 days of laboratory confirmation of severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) infection was investigated [32]. The researchers assessed the overall clinical status of patients, defined as COVID‑19‑related hospitalization or death from any cause at 30 days in a sample of more than 1,000 randomized patients who received bamlanivimab‑etesevimab or placebo. The mean age of patients exceeded 50 years, but more than 50% were adolescents and women. At the end of follow‑up, 2% of patients in the bamlanivimab‑etesevimab group required hospitalization for COVID‑19, compared with 7% in the placebo group. The relative risk difference was 70% and was significantly higher in the placebo group. No deaths were recorded in the group of COVID‑19 patients who received bamlanivimab‑etesevimab mAb injections, while in the comparator group it was 1.7%. At day 7 of follow‑up, the group of patients receiving bamlanivimab and etesevimab had a more significant change in log viral load from baseline than patients receiving placebo. The researchers concluded that mAb therapy with the combination of bamlanivimab and etesevimab in high‑risk outpatients led to a reduction in the frequency of COVID‑19‑related hospitalizations and deaths compared to placebo, and also contributed to a reduction in SARS‑CoV‑2 viral load [32].

One fragment of the US multicenter randomized trial BLAZE‑1 was performed by staff at Baylor University Medical Center and the Scott & White Baylor Research Institute (Dallas, TX, USA). The authors Gottlieb RL et al. (2021) evaluated the effect of bamlanivimab as monotherapy or in combination with the mAb etesevimab on viral load in patients with mild to moderate COVID‑19 [33]. The study aimed to investigate the effect of bamlanivimab monotherapy and combination therapy with bamlanivimab and etesevimab on viral load and SARS‑CoV‑2 infection. More than 610 patients with mild to moderate COVID‑19 were enrolled. Data were analyzed from a study conducted at 49 US centers involving outpatients who tested positive for SARS‑CoV‑2 infection and had one or more mild or moderate symptoms of the disease. In the first stage, patients receiving bamlanivimab monotherapy or placebo were included, and then data from COVID‑19 patients receiving bamlanivimab and etesevimab or placebo were analyzed. All patients were randomized in groups of 100 to receive a single infusion of bamlanivimab at doses of 0.7, 2.8, or 7.0 g, and 110 patients received combination therapy with mAbs and injections of 2.8 g bamlanivimab and 2.8 g etesevimab. The placebo effect was assessed in 150 infected individuals. Change in SARS‑CoV‑2 viral load was determined after 10 days of observation. Nine prespecified secondary outcomes were studied over time by comparing each treatment group with placebo, as well as three viral load measures, five symptoms, and one clinical outcome (proportion of patients hospitalized or visiting the emergency department, or death on day 29 from COVID‑19 complications). As a result, the researchers found that the change in log viral load from baseline at day 11 after intervention ranged from –3.5 to –4.1 in the groups with different drug dosages (700‑2800‑7000 mg). Among secondary efficacy outcomes, differences between each treatment group and the placebo group were statistically significant for 10 parameters and symptoms out of 84 endpoints. The percentage of patients referred for hospitalization or emergency department visits due to COVID‑19 was 5.8% in the placebo group and was significantly lower (0.9–2.0%) in the groups with different drug dosages and 0.9% in the combination therapy group. Among the adverse effects of mAb therapy, the researchers noted an immediate‑type hypersensitivity reaction reported in 9 patients (6 in the bamlanivimab group, 2 in the combination therapy group, and 1 in the placebo group). No deaths occurred during the study. The authors concluded that among outpatients with mild to moderate COVID‑19, treatment with bamlanivimab and etesevimab compared with placebo was associated with a statistically significant reduction in SARS‑CoV‑2 viral load at 11‑day analysis; while bamlanivimab monotherapy showed no significant difference in viral load reduction. The researchers consider it promising to conduct clinical trials evaluating the efficacy of anti‑spike neutralizing monoclonal antibodies not only for preventing disease progression in outpatient settings but also in hospitalized patients with severe complications of COVID‑19 [33].

The US multicenter study REGN‑COV2, using a neutralizing antibody cocktail in outpatients with COVID‑19, organized and coordinated by R. Pharmaceuticals (Tarrytown, NY, USA), evaluated the efficacy of combination therapy with mAbs in outpatients with COVID‑19 [34]. To accomplish the study objectives, all patients were randomized to receive placebo or REGN‑COV2 mAb at low or high dose. Eligible participants were aged at least 18 years and had no indication for inpatient treatment. All had confirmed SARS‑CoV‑2 infection with a positive SARS‑CoV‑2 test before randomization and presence of viral symptoms that appeared no later than 7 days before randomization. Initially, the efficacy of mAb use was assessed in a subgroup of patients with negative test results for three antibodies: IgA, IgG against the S1 domain of the spike protein, and IgG against the nucleocapsid protein. Individuals with positive test results were randomized as having antibodies to the virus. The treatment used a mAb cocktail from the antibodies contained in the REGN‑COV2 preparation, which contains casirivimab (REGN10933) and imdevimab (REGN10987); it was administered in equal doses as a mixture intravenously. Serum antibodies to SARS‑CoV‑2 were tested in all participants, and the two components of REGN‑COV2 were measured in serum. Two human neutralizing monoclonal antibodies against the spike protein of SARS‑CoV‑2 used in the combination cocktail (REGN‑COV2) were measured to reduce the risk of emergence of treatment‑resistant mutant viruses. The analysis included data from a sample of 275 patients. It was found that in the groups receiving the combination dose of REGN‑COV2, compared with patients receiving placebo, the change in viral load adjusted for time of treatment was –0.55 log10 copies per ml, and among patients with negative baseline serum antibody test it was 27% lower (–0.40 log). In the overall study group, 6% of patients in the placebo group and 3% of patients in the combination dose REGN‑COV2 groups required physician consultation (visit) due to symptoms such as hypothermia and rhinobronchopulmonary symptoms, while in the group with negative baseline serum antibody test the corresponding symptoms and need for consultation were 15% and 6%, respectively, with significant difference. The percentage of patients with hypersensitivity reactions, infusion‑related reactions, and other adverse events was similar in the combination dose REGN‑COV2 and placebo groups. The researchers concluded that the REGN‑COV2 antibody cocktail reduced viral load, with a more pronounced effect observed in patients whose immune response had not yet been initiated or who had a high baseline viral load [34].

Another fragment of the US multicenter study REGEN‑COV was presented in a publication by its coordinators, staff of the Department of Medicine and Microbiology at the University of Pennsylvania (Philadelphia, PA, USA), O'Brien et al. (2021) [35]. The study results indicated that the combination of monoclonal antibodies casirivimab and imdevimab significantly reduced the risk of hospitalization or death among individuals at high risk of coronavirus disease 2019 (COVID‑19), but the potential for subcutaneous administration of this REGEN‑COV mAb combination to prevent SARS‑CoV‑2 infection and subsequent development of COVID‑19 in high‑risk individuals who had household contact with an SARS‑CoV‑2 carrier needed verification and clarification. The researchers randomized patients aged over 12 years who were enrolled within 96 hours after household contact with individuals diagnosed with SARS‑CoV‑2. Patients received REGEN‑COV mAb or placebo by subcutaneous injection according to randomization. The primary efficacy endpoint was the development of symptomatic SARS‑CoV‑2 infection by day 28 in participants without SARS‑CoV‑2 infection confirmed by quantitative reverse‑transcriptase polymerase chain reaction or baseline seronegative status. In this study, symptomatic SARS‑CoV‑2 infection developed in only 1.5% of patients who received REGEN‑COV mAb therapy compared with 7.8% in the placebo group, with a significant reduction in relative risk of infection of 80%. During weeks 2 to 4 after mAb administration, the relative risk reduction for disease was more than 90%. The REGEN‑COV cocktail also prevented symptomatic and asymptomatic infection overall in the group, with a relative risk reduction of more than 60%. Drug use in infected patients was associated with a reduction in time to symptom resolution — two weeks shorter than with placebo — and the duration of high viral load was significantly shorter. The authors did not observe an increase in toxic effects with increasing dose of REGEN‑COV. They concluded that administration of the REGEN‑COV vaccine prevented symptomatic COVID‑19 infection and asymptomatic SARS‑CoV‑2 infection in previously uninfected individuals who had been in household contact with infected people, and in infected patients it reduced the duration of illness and the duration of high viral load [35].

A press release from Roche summarized the results of the REGN‑COV 2067 study involving non‑hospitalized high‑risk COVID‑19 patients. The study data showed that the mAbs casirivimab and imdevimab, as part of the Ronapreve preparation, improve survival in high‑risk non‑hospitalized COVID‑19 patients by reducing the risk of hospitalization and death. Ronapreve is also used to treat COVID‑19 in adults, adolescents, and children aged 2 years and older weighing at least 10 kg who do not require supplemental oxygen and who are at increased risk of progressing to severe disease. In addition, its ability to retain activity against new virus variants, including the Delta variant, has been demonstrated in preclinical studies [36].

The Committee for Medicinal Products for Human Use of the European Medicines Agency (EMA) issued a scientific opinion under Article 5(3) of Regulation 726/2004 supporting the use of casirivimab and imdevimab as a treatment option for patients with confirmed COVID‑19 who do not require oxygen therapy and who are at high risk of developing severe COVID‑19. A phase II/III study showed that Ronapreve™ (casirivimab and imdevimab) significantly reduces viral load in patients hospitalized with COVID‑19 [36].

In the United States, the FDA in a communication dated August 10, 2021, authorized REGEN‑COV monoclonal antibody therapy for post‑exposure prophylaxis (prevention) of COVID‑19 [37].

Japan was the first country to approve Ronapreve™ for the treatment of mild to moderate COVID‑19. Japan's Ministry of Health, Labour and Welfare (MHLW) based its recommendations on the results of the global phase III REGN‑COV 2067 study involving non‑hospitalized high‑risk COVID‑19 patients, which showed that casirivimab and imdevimab reduced hospitalization or mortality by 70% and symptom duration by four days, as well as on the results of a phase I clinical trial that examined the safety, tolerability, and pharmacokinetics of this mAb in Japanese residents [38].

The mAb drug AZD7442, a combination of human monoclonal antibodies, was developed in the United States by the Vanderbilt University Medical Center in Nashville, Tennessee. AZD7442 is a combination of two long‑acting antibodies (LAABs), tixagevimab and cilgavimab, derived from B cells of patients recovered from SARS‑CoV‑2 infection. It was found to be effective in outpatients for prophylaxis and reduction of disease severity in symptomatic COVID‑19 [39]. This combination of monoclonal antibodies was shown to reduce symptomatic COVID‑19 cases by 77% compared with placebo in the phase III PROVENT trial, a randomized, double‑blind, placebo‑controlled study involving more than 5,000 people. No cases of severe disease or death were recorded among patients receiving the drug. Reduced immune response to vaccination was detected in more than 75% of study participants who had comorbidities. The efficacy of AZD7442 was studied in 87 centers in the United States, United Kingdom, Spain, France, and Belgium. More than 5,000 adult patients were randomized to receive a single dose of AZD7442 300 mg (3,500 people) or placebo — sterile saline injection (1,700 people). In the intervention group, more than 40% of patients were aged 60 years and older, and more than 75% had comorbidities. Analysis at 6 months showed that a single dose of AZD7442 reduced the risk of symptomatic COVID‑19 by 80% compared with placebo. Among participants receiving the mAb combination, no cases of severe COVID‑19 or COVID‑19‑related death were recorded either in the primary or six‑month analysis, whereas five cases of severe COVID‑19 and two deaths were recorded in the placebo group [40].

Another international randomized, double‑blind, placebo‑controlled study of this mAb drug AZD7442 (tixagevimab‑cilgavimab), called TACKLE, coordinated by staff of the Nuffield Department of Primary Care Health Sciences, University of Oxford (Oxford, UK), aimed to evaluate the safety and efficacy of a single 600 mg injection of the drug (in the PROVENT study, 300 mg single dose, half the amount) compared with placebo in non‑hospitalized adults with mild to moderate COVID‑19 and symptom duration of less than seven days. Nearly 900 participants were randomized to receive AZD7442 or placebo (450 each). In the intervention group, only about 10% of participants were aged 65 years and older, but 90% had comorbidities and conditions associated with a high risk of developing severe COVID‑19. According to the analysis, at 30 days after AZD7442 administration, the researchers noted a reduction in the risk of severe COVID‑19 or death (from any cause) of more than 85% compared with placebo in patients who had symptoms for three days or less at the time of treatment initiation [41–43].

It should be remembered that the prescription of any medication involves serious risks, especially without consideration of pharmacodynamics and drug interactions. The following principles should become axioms for the practicing physician:

1. drug therapy should be prescribed only after a confirmed diagnosis and for specific indications according to the drug label;

2. the course and daily dosage regimens must be strictly observed, especially for antihypertensive drugs;

3. possible unfavorable combinations of different drugs when taken concomitantly should be taken into account;

4. the patient's age and the presence of comorbidities must be considered [44].

Thus, to date, the pathogenesis of the virus has not been fully elucidated, but the theory of systemic inflammation as the main damaging factor of viral infection dominates in global medical practice [45].

The use of the combination of neutralizing monoclonal antibodies casirivimab and imdevimab in the randomized, placebo‑controlled trials BLAZE‑1 and REGEN‑COV was associated with reductions in viral load and the frequency of hospitalizations and emergency department visits among outpatients with COVID‑19. In the PROVENT and TACKLE studies using the mAb drug AZD7442, consisting of two long‑acting antibodies, tixagevimab and cilgavimab, a reduction in the risk of severe COVID‑19 or death from any cause of more than 85% was observed in outpatients compared with placebo, demonstrating its high antiviral activity.