key: cord-0968242-b4xix0u1
authors: Deb, Paroma; Molla, Md. Maruf Ahmed; Rahman, K.M. Saif-Ur
title: An update to monoclonal antibody as therapeutic option against COVID-19
date: 2021-02-10
journal: Biosaf Health
DOI: 10.1016/j.bsheal.2021.02.001
sha: 9f9b3a84a9d28219d636d20777f112d2e83f23e4
doc_id: 968242
cord_uid: b4xix0u1

With the number of COVID-19 cases soaring worldwide and limited vaccine availability for the general population in most countries, the monoclonal antibody (mAb) remains a viable therapeutic option to treat COVID-19 disease and its complications, especially in the elderly individuals. More than 50 monoclonal antibody-related clinical trials are being conducted in different countries around the world, with few of them nearing the completion of the third and fourth phase clinical trial. In view of recent emergency use authorization (EUA) from the FDA (Food and Drug Administration) of casirivimab and imdevimab, it is of importance that mAbs, already used to treat diseases such as Ebola and respiratory syncytial virus (RSV), are discussed in scientific communities. This brief review discusses the mechanism of action and updates to clinical trials of different monoclonal antibodies used to treat COVID-19, with special attention paid to SARS-CoV-2 immune response in host cells, target viral structures, and justification of developing mAbs following the approval and administration of potential effective vaccine among vulnerable populations in different countries.

Since the emergence of novel coronavirus SARS-CoV-2 in late December 2019, morbidities and fatalities are still increasing worldwide, with reports of re-infections coming along. 1 Inspite of significant efforts that have been directed towards developing an effective therapeutic intervention against COVID-19, no therapeutic agent has been approved for treating as of writing this review. Even though several vaccines have received EUA in different countries, people in general in most countries still have to rely on traditional medications and symptomatic management of the disease. Recent underwhelming results of the World Health Organization (WHO) solidarity trial has again proved our helplessness against this disease with our existing medications. 2 The invention of new modalities of treatment, in addition to a safe and effective vaccine, is now an urgent need to combat this pandemic.

Immunotherapy in the form of vaccine or antibody therapy etc. has proved its effectiveness against viral infectious diseases in earlier cases. Intervention with convalescent plasma from recovered patients or hyper-immune immunoglobulin from the patients who were previously infected with influenza, SARS, MERS, and Ebola, which contains a sufficient amount of antibody is likely to reduce the viral load and ultimately lead to reduced disease mortality. 3 However monoclonal antibodies (mAbs) represent a form of passive immunotherapy, which can provide an efficient therapeutic intervention against a particular disease. Besides, mAbs are far more specific, precise, and safe in comparison to conventional convalescent plasma therapy as these antibodies can be isolated from the blood of the infected patients or can be engineered in the laboratory. 4 While a safe and effective COVID-19 vaccine, to date, remains the best option to fight off this pandemic, mAbs can be helpful, especially in settings such as care homes and places where rapid dissemination of infection is taking place. 5 This brief review discussed J o u r n a l P r e -p r o o f Journal Pre-proof different mAbs including a brief account of the immune response in SARS-CoV-2, the spike protein structure of SARS-CoV-2the principal target of the mAbs, mechanism of action of mAbs, how they fare against an effective vaccine and update to COVID-19 clinical trials involving mAbs.

For this brief review, articles discussing mAbs in regards to COVID- 19 

The mAbs are likely to aid in reducing viral load by interfering with virus entry into a cell by binding to viral spikes and thus inhibiting virus attachment to cell surface receptors or by targeting host cell receptors or co-receptors, thereby making the binding sites of host cells unavailable for SARS-CoV-2. Alternatively, they can act as immunosuppressive agents, limiting immune-mediated damage, and play a role in reducing morbidity and mortality. 6 In the following J o u r n a l P r e -p r o o f Journal Pre-proof section the review will discuss mAbs directed against different parts of SARS-CoV-2 that received current EUA or undergoing various stages of the clinical trials.

After entering the body, SARS-CoV-2 first activates the innate immune response, and then the adaptive immune responses after a few days. According to immune responses, clinical phases of SARS-CoV-2 infection are the viremia phase, the acute phase (also known as pneumonia phase), and the recovery phase. Studies showed that in the high-risk group with COVID-19, local tissue inflammation and systemic cytokine storm is responsible for the sepsis caused by the virus, and pneumonitis, inflammatory lung injury, acute respiratory distress syndrome (ARDS), respiratory failure, shock, organ failure, and potential death are the consequences of aberrant host immune response. [7] [8] [9] [10] The S proteins of SARS-CoV and SARS-CoV-2, two similar viruses, have an amino-acid sequence identity of around 77% with around 89.8% sequence identity in S2 subunits. 8,11 These similarities have helped researchers in repurposing neutralizing mAbs directed against SARS-CoV S-protein or host angiotensin-converting enzyme 2 (ACE-2) receptors for SARS-CoV-2,

although several studies showed a range of discrepancies about how these neutralizing antibodies work. For example, antibodies, CR3002, and F26G19 interact with SARS-CoV by binding with their receptor-binding domain (RBD), whereas, in SARS-CoV-2 they target epitopes other than the RBD, which compete with ACE2 and neutralize the virus more potently than SARS-CoV. 12,13 Several such antibodies are now as work in progress for SARS-CoV-2, namely, 2B2, severe disease. 17 The EUA was granted after it was observed that disease progression was slower in patients who received bamlanivimab than that in those receiving placebo in phase two randomized, double-blind, placebo-controlled clinical trial in 465 non-hospitalized adults. 18 Two other anti-spike mAbs, which are now in phase 3 clinical trials, are LY3819253 + LY3832479, and VIR-7831/GSK4182136. The first one has enrolled 2,400 healthy staff or residents of a nursing facility and 10,000 hospitalized patients as their study population. The second one has enrolled 1,360 non-hospitalized high-risk patients as the receiver of antibody doses. There are several other mAbs targeting S-protein are now in the phase-1 trials, namely, BGB-DXP593, JS016, CT-P59, BRII-196 and 198, SCTA01, MW33, COVI-GUARD/STI-1499, AZD8895 + AZD1061, and HLX70. 19 

In the case of SARS-CoV-2, granulocyte-macrophage colony-stimulating factor (GM-CSF) produced by activated CD4+ T cells and interleukin-6 (IL-6) play a central role in immunopathogenesis. 20 After binding of SARS-CoV-2 to alveolar epithelial cells, production of a range of proinflammatory cytokines and chemokines, including GM-CSF and IL-6 occur, which in turn recruit more monocytes and macrophages and lead to a subsequent cytokine storm. 21 23) , is now at phase-2. 29 A case-control study showed 80% reduction in relative risk of invasive ventilation and/or death in patients treated with lenzilumab compared with the control group. 30 In addition, the median time to resolution of ARDS reduced to one day along with early discharge from the hospital for patients treated with lenzilumab versus eight days to resolution, and double-time before discharge for the control group was observed. 30 Table   1 . is "target specificity" and hence optimum timing of therapy for a specific disease with a mAb must be validated based on clinical stages of that certain disease. 33 For instance, bamlanivimab, the target of which is SARS-CoV-2 spike protein, has been recommended for use within 10 days after onset of symptoms but best suited for use in patients immediately after confirmed virological diagnosis of SARS-CoV-2. 17, 18 On the other hand, Tocilizumab, anti-IL-6 mAb, is indicated for use in more critical patients with COVID-19 pneumonia and those requiring ventilator support. 34 On a general note, when considering infectious diseases, three particular indications are here for their use, namely; treatment of infected individuals, prophylaxis for highrisk individuals (e.g. pregnant women in the Zika endemic regions) for the patient-level outcome, and prophylaxis to interrupt transmission in average-risk population to achieve population-level outcomes. 35 Although mAbs are one of the fastest-growing drug classes in the modern era, the precise mechanism by which they achieve their therapeutic effect is yet to be known. Any biological response or outcome with therapeutic mAb depends on several variables. Among them, antigen cell-surface density, their tissue distribution along with specificity, avidity, and isotype of any given mAb play a major role. To overcome limitations and to improve therapeutic effects relentless efforts are being made and hence, after chimeric and humanized mAb, bioengineered human antibodies are showing new prospects. 36 As of writing this paper, more than 75 monoclonal antibodies have been developed and approved by the FDA for use in different diseases. 5 But only three of them are being used to treat J o u r n a l P r e -p r o o f infectious diseases: RSV, anthrax, and clostridium difficile. 5 More recently, two monoclonal antibodies (MAb114 and REGN-EB3) were tested against Ebola virus disease and the results were encouraging. 37 The reason behind such slow speed in developing monoclonal antibodies against virus diseases include unreasonable costing associated with research and development, especially when compared with alternative preventive and therapeutic strategy such as small molecule drugs and vaccines. Additionally, the complexity and ambiguity of viral pathogenicity and infections as well as the rapid mutation of virus make it harder for researchers to formulate effective and long-lasting mAb therapy against viral diseases. 38 Very recently, two mRNA based vaccines developed by Pfizer-BioNTech and Moderna received EUA by FDA with 95% and 94.1% efficacy rate respectively; one adenovirus vectored vaccine Emirates (UAE) and Bahrain. [39] [40] [41] Although these vaccines have been approved for mass vaccination, their long-term effectiveness, any vaccine-related side effects as well as production ability to meet the need of the world population are still to be answered. As a result, monoclonal antibodies will remain a viable alternative to the COVID-19 vaccine for the foreseeable future.

There are more than 50 monoclonal antibodies in different phases of clinical trials in different countries and recently FDA has given emergency use authorization to several monoclonal antibodies including bamlavinimab, casirivimab, and imdevimab -mAbs targeting the spike protein of SARS-CoV-2 virus. One might assume that mAbs are here to stay for the long run but, like most other therapeutic options to treat viral diseases, mAbs have several limitations. Firstly, developing an effective mAb against SARS-CoV-2 requires extensive labor and substantial J o u r n a l P r e -p r o o f financial investment, even if a substantial proportion of groundwork regarding monoclonal antibody development was carried out during the original SARS-CoV epidemic in 2003. 42, 43 Nevertheless if mAbs are developed, their application might become limited once those vaccines are widely available. The primary group for mAb therapy would be a small group of people unable to mount an immune response even after administration of a suitable vaccine such as the elderly population or immune-compromised patients, which might not justify the large financial outlay. 44 Secondly, viruses are prone to frequent mutations as experienced in cases of HIV and HCV. Hence, monoclonal antibodies directed against the S-protein and the receptor-binding domain (RBD) might lose their efficacy if there is a mutation followed by a conformational change in antigen epitope, resulting in reduced inhibition of viral replication. 45 In addition to that, establishing a target population has proven to be troublesome with most people with clinical infections who recovered without administration of mAb, making it harder for researchers to establish a clinical endpoint compared with placebo. 19 Besides, in patients suffering from severe diseases, reducing viral replication might not always be the priority as other pressing issues such as inflammation and coagulopathy which might require urgent attention. 19 To summarize, monoclonal antibodies are effective, as evidenced from studies conducted on plasma therapy against COVID-19, as post-exposure prophylaxis to prevent severe diseases or complications.

Hence, mAbs may still have important roles, albeit in a small group of people, in treating patients admitted to intensive care units or for those who did not respond to a vaccine. 19 But for that funding must be secured from non-profit donors or else, the development of SARS-CoV-2 specific mAbs can come to a halt sooner than expected. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-updatefda-authorizes-monoclonal-antibodies-treatment-covid-19, 2020 (accessed 2 February 2021).

[16] Weinreich, D., Sivapalasingam, S., Norton, T., Ali, S., Gao, H., Bhore, R., et al. 

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