An update to monoclonal antibody as therapeutic option against COVID-19

Abstract

1. Introduction

Since the emergence of novel coronavirus severe acute respiratory syndrome coronavirus 2 (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 COVID-19 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 different mAbs including a brief account of the immune response in SARS-CoV-2, the spike protein structure of SARS-CoV-2 – the 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.

2. Methodology

For this brief review, articles discussing mAbs in regards to COVID-19 treatment were searched and downloaded from publicly available databases including PubMed and Google Scholar. Key search terms and phrases included: SARS-CoV-2, COVID-19, coronavirus, mAb, monoclonal antibody, antibody treatment, monoclonal antibody clinical trial, etc. Key search terms were used both separately and in combination with other ones. Articles deemed relevant to the topic, published up to December 30, 2020 were included in this review. There was no specific requirement regarding article formats, so that all relevant literatures including comprehensive review, original study, clinical trials, perspectives, and editorials were considered as long as their topic was within the scope of this review. Regarding clinical trials involving mAbs, registries such as www.clinicaltrials.gov were searched by the authors, and mAbs undergoing phase 2, 3, and 4 clinical trials were included within this review.

3. Monoclonal antibody against SARS-CoV-2: update to clinical trials

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 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.

4. Future prospect of monoclonal antibodies

Development procedures of any mAb need to follow a stringent guideline approved by the World Health Organization (WHO). In all cases, both non-clinical (in-vitro and in-vivo animal model study) and clinical evaluations should be performed. The focus of these studies primarily remains on pharmacokinetics (PK), pharmacodynamics (PD), and safety, and when passed, leads into pivotal clinical trials. Antibodies act through a variety of mechanisms ranging from receptor blockade to apoptosis by immune-mediated mechanisms (e.g. CDC, ADCC, and regulation of T cell function) [33]. Therefore, researchers have to take several factors into consideration before using them in any clinical setting. A homogeneous group of patients with the same line(s) of therapy or severity or stage of disease progression, and those receiving first-line therapy are considered to be the ideal candidate for mAb therapies. Another main attraction for mAb therapy 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 high-risk 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 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 ChAdOx1 nCoV-19 (AZD1222) developed by Oxford-AstraZeneca with 70.4% efficacy rate received approval from the UK; and lastly one inactivated virus vaccine developed by Sinopharm received approval from China, with 79.34% efficacy rate in The United Arab 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 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.

5. Conclusion

In conclusion, monoclonal antibodies are, and will most likely continue to be, important therapeutic options going into the 21st century, not just for SARS-CoV-2 but also for other infectious pathogens too. Efforts should be directed towards developing monoclonal antibodies that are highly effective, can be developed by a fraction of a current cost, and for whom there is a specific beneficiary group.

Conflict of interest statement

The authors declare that there are no conflicts of interest.

Author contributions

Paroma Deb: Conceptualization, Data Curation, Writing - Original Draft. Md. Maruf Ahmed Molla: Conceptualization, Data Curation, Writing - Original Draft. K.M. Saif-Ur-Rahman: Conceptualization, Methodology, Writing - Review and Editing.

References