Introduction

Worldwide, the Coronavirus disease 2019 (COVID-19) outbreak due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to global public health crisis and an urgency for effective, preventive and therapeutic life-saving measures (Marovich et al., 2020). This novel ß-coronavirus has infected more than 134 million individuals, and killed approximately 2.9 million globally (Valdez-Cruz et al., 2021).

Several prophylactic and therapeutic strategies are being considered and designed during this pandemic to combat the SARS-CoV-2 (Taylor et al., 2021). Based on the increasing needs in the healthcare system, more focus has been directed towards the development of potent antiviral agents, convalescent plasma infusions, and vaccines. Neutralizing monoclonal antibodies (mAbs) to SARS-CoV-2 can stimulate protective immunity (Marovich et al., 2020). Hence, their rapid identification and characterization are incorporated in clinical practice to provide effective treatment and prophylaxis (Valdez-Cruz et al., 2021). Some of the clinically developed and currently used mAbs in the treatment of COVID-19 has been listed (Table 1).

SARS-CoV-2 Antibodies

Antibodies are naturally produced proteins released by the immune system in response to specific infections. Whereas, monoclonal antibodies are laboratory developed proteins especially designed to mimic or enhance the body’s natural immune system to fight against targeted pathogens such as viruses (Lloyd et al., 2021). These recombinant proteins can bind to and ‘neutralize’ the virus in COVID-19-positive patients; thus, serving as front line, anti-viral agents amidst the pandemic (Lloyd et al., 2021).

SARS-CoV-2 infected patients can be treated with antibodies using various mechanisms. Convalescent plasma (CP) extracted from recovered COVID-19 individuals consists of polyclonal antibodies with varying diversity and affinity to the SARS-CoV-2 infection (Scourfield et al., 2021). Neutralizing mAbs can be derived by isolating the memory B cells of convalescent patients with high-neutralization capacity or immunized animals, and screening of antibody mRNA (Taylor et al., 2021; Scourfield et al., 2021).

COVID-19 therapeutic mAbs can be categorized into anti-virus and anti-host groups based on their specific targets (Ning et al., 2021). Neutralizing responses to SARS-CoV-2 basically targets the receptor-binding domain (RBD) of the spike (S) glycoprotein, which is responsible for target receptor angiotensin-converting enzyme 2 (ACE2) interaction. Thus, steric hindrance of the RBD-ACE2 interaction via antibodies helps in preventing infection by blocking the viral attachment or entry into human host’s cells (Scourfield et al., 2021). Therefore, majority of the direct anti-viral mAbs target the spike protein of SARS-CoV-2 as it mediates the virus entry, and affects the CP therapy which is dependent on the titre of neutralizing anti-spike antibodies (Ning et al., 2021). Host factors involved in the pathogenesis of COVID-19 or the life cycle of SARS-CoV-2 are also potent targets as it does not only exert anti-viral and anti-inflammatory effects but also deals with the complications caused by SARS-CoV-2 infection (Ning et al., 2021).

Prior to the COVID-19 pandemic, mAbs have been used for several other viral infections including Ebola, influenza, HIV, RSV, Zika virus, and MERS-CoV (Monoclonal antibodies, 2021). The mAbs are effectively used in anti-viral interventions since they are specifically designed by exposing a white blood cell to a particular viral protein, and cloned to produce a massive army of antibodies to target that unique virus (Lloyd et al., 2021). The U.S. Food and Drug Administration (FDA) has recently granted emergency use authorizations (EUA) for the application of neutralizing mAbs in COVID-19 patients with mild-to-moderate symptoms who do not require hospitalization (Taylor et al., 2021).

Tocilizumab, an anti-host monoclonal antibody that effectively targets the cytokine interleukin 6-receptor (IL-6R) has been the first monoclonal drug used for treating patients with severe COVID-19 (Ning et al., 2021; Zhou and Wei, 2020). The hyperactivation of IL-6 may play a major role in the pathophysiology of severe COVID-19 infection; hence, targeting the anti-inflammatory agents could provide additional treatment efficacy (Gupta and Leaf, 2021).  Findings from the clinical trials indicate reduced hospital stay and improved clinical outcomes in patients treated with tocilizumab (Zhou and Wei, 2020). 

On the other hand, bamlanivimab (also known as LY-CoV555 and LY3819253) is an anti-virus mAb that targets the RBD of the S protein of SARS-CoV-2. While, another type of neutralizing mAb called etesevimab binds to a different but overlapping epitope of the S protein RBD of SARS-CoV-2. Furthermore, casirivimab and imdevimab are recombinant human mAbs that bind to non-overlapping epitopes in the RBD of SARS-CoV-2 S protein (NIH, 2021).

Previous literature indicates that the monotherapy of bamlanivimab in patients with mild-moderate COVID-19 had a curtailing effect on mortality and hospitalization within 28 days (Bariola et al., 2021). In fact, when bamlanivimab, bamlanivimab together with etesevimab, and casirivimab with imdevimab are given early on in the course of SARS-CoV-2 infection, it decreases the viral load and shows favourable clinical outcomes based on data from the ongoing clinical trials (Taylor et al., 2021).

Another recent human mAb, approved for an early treatment option for COVID-19 is sotrovimab (GSK4182136 and VIR-7831). This genetically engineered anti-SARS-CoV-2 antibody has been derived from the cross-reactive S309 mAb, and designed for an extended half-life and improved bio-distribution in the lungs (Corti et al., 2021). It is expected to reduce the rate of hospitalization COVID-19 patients by effectively attaching to the spike protein of SARS-CoV-2, and diminishing the virus' entry into host cells (EMA, 2021).

Sotrovimab is currently being investigated in a Phase 1/2/3 randomized, double-blinded, placebo-controlled clinical trial among the SARS-CoV-2 infected, non-hospitalized patients presenting mild-to-moderate symptoms (The Antibody Society, 2021). Patients at an early-stage of COVID-19 with a higher risk of hospitalization (aged =55 years with pre-existing lung or cardiovascular disease) were intravenously administered a 0.5 g single dose of sotrovimab (Corti et al., 2021). The FDA EUA was granted based on the interim analysis on 583 COVID-19 patients who recently had onset of symptoms from the SARS-CoV-2 infection. Interestingly, it was deduced that hospitalization or death occurred in 3 (1%) patients treated with sotrovimab in comparison to 21 (7%) patients who received placebo (The Antibody Society, 2021). The Phase III COMET-ICE trial involving adult outpatients with an increased risk of COVID-19 disease progression, reported 85% reduction in hospitalization for over 24 hours and/or death in participants who received sotrovimab versus placebo (Pharmaceutical Techonology, 2021).

The anti-SARS-CoV-2 mAbs are contraindicated in severe COVID-19-related hospitalized patients who require increased oxygen flow rate and/or require chronic oxygen therapy due to any underlying non-COVID-19-related comorbidities. However, the utilization of mAbs are permitted in patients with mild-moderate SARS-CoV-2 infection, and particularly those who are at high risk of hospitalization and/or for progression to severe COVID-19 (FDA, 2021).

According to a research by the University of Pittsburgh Medical Center (UPMC), monoclonal antibodies helped in mitigating the risk of mortality and hospitalization up to 60% when provided as an early therapeutic and prophylactic measure for the coronavirus infected patients (UPMC, 2021). Nevertheless, administering mAbs such as casirivimab and imdevimab to the hospitalized COVID-19 patients who require high flow oxygen or mechanical ventilation may lead to worse clinical outcomes (FDA, 2021).

There are also possible adverse reactions including both allergic or non-allergic infusion-related reactions. Itching, flushing, low blood pressure and shortness of breath are some of the rare infusion-related reactions. While soreness, pain, and bruising around the intravenous site are some of the potential side effects of administering IV medication (Chen et al., 2021). Diarrhoea and rash were major adverse events observed in patients treated with sotrovimab (Pharmaceutical Techonology, 2021).

The ‘Coronavirus Treatment Acceleration Program’ (CTAP) is on a constant surge to develop safely effective and novel therapies by utilizing every possible pathway to curb the viral effects and treat the COVID-19 infection FDA, 2021). Currently, more than 50 mAbs are being processed at different developmental stages against SARS-CoV-2, and majority of these are directed against the spike protein (Deb et al., 2021). It is necessary to investigate the neutralizing mAb treatment benefits on at-risk population, protection period of the mAbs, effect on subsequent vaccination, and optimum timing for mAb administration based on the serology, viral load and other clinical factors (Taylor et al., 2021).

As the number of infected cases are soaring globally at an alarming rate, several other factors related to the anti-viral mAbs should also be considered. Due to the increasing demands and limited medical resources, administration of mAbs might be a difficult task during the pandemic. Firstly, because these drugs are expensive, and secondly as the infusion has to be carried out in specialized medical centres. There has also been mixed reporting regarding the benefits of mAbs among hospitalized patients with COVID-19, while many researchers anticipated that mAb treatment might work best during the early onset of infection rather than a late-stage with severe symptoms and complications (Nature, 2021). However, the human monoclonal antibody prevails as a viable therapeutic approach in most countries that are currently facing inadequate vaccine availability for their general population (Deb et al., 2021).

Furthermore, prophylactic or therapeutic use of the mAbs could have better utility among those with poor immune response to vaccination, elderly, and/or vaccine refractory individuals (Deb et al., 2021; Case et al., 2021). Due to emergence of mutated SARS-CoV-2 strains, modified mAb patterns and adjusted spike sequences of vaccines might have to be reformulated for effective immune protection from COVID-19 (Nature, 2021). The stability, production capacity, prevention of resistance, possible synergy in antibody combination, mechanism of neutralization, the role and optimization of Fc effector functions needs to be considered for evaluation as more human mAbs are being tested and developed (Case et al., 2021). 

Concluding Remarks and Future Perspectives

Several clinical trials are still underway to evaluate the efficacy, pharmacokinetics, safety, and tolerance of various mAbs (Jaworski, 2021). This indicates the limited body of scientific evidence or published data to support the clinical efficacies of these therapeutic agents, thus questioning the possible short and long-term implications of mAbs. Furthermore, the development of multiple mAbs is associated with high-cost implications and is a leading barrier to their usage in therapeutic settings (Jaworski, 2021). It can be a potential drawback, so healthcare organizations should question how to address the affordability and economic burden revolving around the use of mAbs.  The longevity of mAbs is another area of discussion occurring due to the advent of the SARS-CoV-2 variants of concern (VOC) with mutating spike protein near the binding epitope and leading to viral resistance (Razonable & Chen, 2022). According to preclinical research, COVID-19 treatment and prevention may benefit from combinations of powerful mAbs that target the SARS-CoV-2 receptor binding site as well as broad mAbs that target conserved areas of the viral spike (Jaworski, 2021). Therefore, collective efforts should focus on queries related to overcoming the issue of viral resistance and enhancing the use of cocktail mAbs for increased prophylaxis.

Since most of the interim results on anti-SARS-CoV-2 related mAbs are based on ongoing clinical trial data, several questions, as discussed above, revolve around this novel therapy, mostly involving its long-term implication, application, and feasibility. Although, the use of neutralizing mAbs may assist in alleviating the critical burden on healthcare settings, and minimizing hospital stay due to severe progression of COVID-19 symptoms. Nonetheless, there is a broader need for future studies to explore these novel therapies for their effective use in clinical practice and to improve patient-related outcomes.

Author Contributions

The conceptualization process involved MC and SH. Survey of literature was carried out by MC, SH, and TS. Manuscript drafting and editing was done by SH, TS, and MC. Critical review, validation, and supervision were performed by MC, KM, and PKR. All authors have read and agreed to the published version of this manuscript.

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