Tuesday, 19 October, 2021

Monoclonal Antibodies– A Game Changer to Fight Coronavirus

Rashidul Haque, PhD and Tarannum Naz, PhD

Monoclonal Antibodies– A Game Changer to Fight Coronavirus

Recently, the World Health Organisation (WHO) has approved an emergency use of REGEN-COV, a cocktail of monoclonal antibodies (mAbs) – Casirivimab and Imdivimab – developed by the US biotechnology company ‘Regeneron Pharmaceuticals’ to prevent severe acute respiratory syndrome of coronavirus 2 (SARS-CoV-2) infections and treat Coronavirus Disease 2019 (COVID‑19). Monoclonal antibodies are laboratory-made versions of proteins naturally produced by the immune system in response to invading viruses or other pathogens. The neutralising ‘mAbs’ to SARS-CoV-2 have the potential for both therapeutic and prophylactic applications, and have been shown very effective in preventing COVID-19. In a placebo-controlled trial of COVID-19 patients, a combination of Casirivimab and Imdivimab ‘mAbs’ were shown to markedly reduce COVID-19-related hospitalisation or death among high-risk persons. Other preclinical and clinical studies showed consistent effectiveness of REGEN-COV against current variants of SARS-CoV-2.  However, WHO predicts that this may be difficult to manage ‘mAbs’ in low- and middle-income countries (LMICs) due to its high cost and lack of necessary equipments. This type of immunotherapy using ‘mAbs’ has previously been successful in suppressing HIV (Human Immunodeficiency Virus), Ebola and RSV (Respiratory Syncytial virus) viruses.

Based on a randomised, double-blind, placebo-controlled clinical trial in 799 non-hospitalised adults with mild to moderate COVID-19 symptoms, the US Food and Drug Administration (FDA) approved an initial Emergency Use Authorization (EUA) for REGEN-COV to treat COVID-19 adults and paediatric patients (12 years of age or older) with exposure to SARS-CoV-2 at high risk for progression to severe COVID-19. Later, the FDA updated its EUA for REGEN-COV for its emergency use as post-exposure prophylactic to prevent COVID-19 progression in adults and children aged 12 years or older. Subsequently, the therapeutic ‘mAbs’ therapies have undergone accelerated approvals worldwide for the treatments to reduce the severity of COVID-19. Recently, India has also given EUA for a COVID-19 antibody drug cocktail developed by Roche and Regeneron.

REGEN-COV is an effective inhibitor of a combination of two ‘mAbs’ (Casirivimab and Imdivimab) used against early treatment of COVID-19 and the recommended dose for each antibody is 600 mg. This ‘mAb-cocktail’, administered together by intravenous (IV) infusion, might offer immediate protection from infection. REGEN-COV is not approved for use as a ‘pre-exposure prophylaxis’ to prevent possible COVID-19 before being infected by the SARS-CoV-2 virus; rather it can only be applied as an antidote if one infected with the coronavirus. However, REGEN-COV should not be used by people who suffer from severe allergic reactions. In addition, two other ‘mAbs’ –  Bamlanivimab/Etesevimab cocktails manufactured by the company "Eli Lilly" and the ‘mAb’ Sotrovimab from GlaxoSmithKline (GSK) – were also approved by the US FDA for the early treatment of COVID-19. A cocktail of two antibodies, Bamlanivimab and Etesevimab has been demonstrated to cut the risk of hospitalisation and death by 87%.

In 2020-21, more than 9,600 hospitalised COVID-19 patients were given ‘mAbs’ treatment as part of a 'recovery' drug trial. Oxford University scientist Sir Martin Landre, the lead investigator, showed in their study that the antibody-cocktail treatment was the first of its kind in Britain to save the lives of COVID-19 patients in hospital. In addition, the new ‘mAbs’ therapy at Sir Ganga Ram Hospital in New Delhi has dramatically cured COVID-19 patients as a ‘game-changer’ in just 12 hours.

Other studies have also shown that if a patient is administered a cocktail of ‘mAbs’ immediately after SARS-CoV-2 infection, the antibody-cocktail may markedly increase the patient's immunity. It has been found that the application of REGEN-COV cocktail within 10 days of the initial symptoms of coronavirus infection has resulted in a reduction in hospitalisation and mortality of patients by about 60%. In addition, the risk of infection among the patient's family members may be less than 60%. However, this cocktail should not be used for patients who are on oxygen therapy due to COVID-19. Neither any serious side effects, nor any potentially fatal allergic reactions (such as anaphylaxis) have been reported from this drug.

Our immune system is composed of a complex team of players that detect and destroy disease-causing agents, such as bacteria and viruses. Similarly, this system may eliminate damaged or abnormal cells, such as cancer cells as well. The "B-lymphocyte" of the human body's immune system makes antibodies. The immune system naturally produces two types of antibodies: 'monoclonal' or 'polyclonal' antibodies. Polyclonal antibodies are a mixture of antibodies that are secreted by different B cell lineages or clones. These antibodies are actually a collection of immunoglobulin (IgG) molecules that react against a specific antigen or foreign protein, each identifying a different epitope (the part of an antigen that is recognised by the antibody) on an antigen/protein. In contrast, ‘mAbs’ are laboratory-made proteins that mimic the immune system’s ability to fight off harmful pathogens such as viruses. They (mAbs) are made from the same lineage of B-lymphocyte cells, so that the antibody is able to bind to the same epitope or location of a specific protein or an antigen of a bacterium or virus. With the discovery of a special molecular biology technology called “hybridoma”, it is now possible to produce ‘mAbs’ that specifically bind to virtually any suitable antigen. For example, the spike protein – or a specific part of it – of coronavirus is injected into a rat and causes specific B-lymphocytes from its spleen to attach to the “myeloma” (a type of cancer of the blood plasma cell) tumor cell to make a ‘hybridoma cell-line’. Casirivimab and Imdivimab are such ‘mAbs’ that are specifically directed against the spike protein of SARS-CoV-2, designed to block the viral attachment and entry into human cells.

In the early part of last century, a concept was developed by Russian scientists Ehrlich and Élie Metchnikoff that a “magic bullet” as a compound selectively targeted a disease-causing organism, which later underpinned the concept of ‘mAbs’ and monoclonal drug conjugates. They received the 1908 Nobel Prize for Physiology or Medicine for providing the theoretical basis for immunology. In 1975, George Köhler and Millstein discovered “hybridoma” technology at the Medical Research Council (MRC) Laboratory of Molecular Biology in Cambridge, UK. They succeeded in making fusions of myeloma cell lines with B cells to create hybridoma that could produce antibodies against a specific antigen, and they received Nobel Prize in 1984 for their achievements in the development of ‘mAbs’. The use of ‘mAbs’ in the treatment of cancer, especially breast cancer, has been a breakthrough in the development of anti-cancer and anti-bacterial therapies, for that Allison and Honjo were awarded the Nobel Prize in Physiology or Medicine in 2018 for their discovery of cancer therapy by inhibition of negative immune regulation, using ‘mAbs’.

Like most natural antibodies, ‘mAbs’ (IgG1) have a ‘half-life’ of about one month, meaning the effectiveness of the antibody is reduced by half after one month. However, research is ongoing to increase the "half-life" of ‘mAbs’ by modifying the "Fc" region of the antibody. In fact, after a coronavirus infection or a COVID-vaccination, our immune system has to wait at least two to three weeks to develop an effective immune response against the virus or an antigen. In addition, two doses of the vaccine are needed to get adequate immune response. In contrast, only one supplementary 'mAbs’ infusion within 10 days of infection can play an active role in immediate virus protection and COVID-19 prevention. That is, ‘mAbs’ binding to a 200 amino acid long region, called ‘Receptor Binding Domain (RBD)’ of the spike protein of SARS-CoV-2. It immediately prevents the virus from entering the human cell by inhibiting the attachment of the virus to Angiotensin Converting Enzyme (ACE)-2 receptors on the human cell surface. SARS-CoV-2 cannot enter human cells without binding to ACE-2 protein. All available and effective COVID-19 vaccines and lab-made ‘mAbs’ have been created to target the ‘RBD’ region of the spike protein. The twin-antibodies (Casirivimab and Imdivimab) are also based on the ‘RBD’ portion of the spike protein of the SARS-CoV-2 virus, making it impossible for the virus to bind to ACE-2 receptor proteins on the human cell surface. Alternatively, ‘mAbs’ may also act as immunosuppressive agents, thereby reducing morbidity and mortality, and also by reducing immune-mediated cytokine-storms prevent damage to the body.

There is no substitute for the vaccine of COVID-19, not do we support ‘mAbs’ as the replacement of vaccine for COVID-19 treatment. So far, the US FDA has approved a total of three vaccines to prevent COVID-19: Pfizer-BioNTech and Oxford-AstraZeneca, Moderna, and Johnson-Johnson. In addition, China's Sinovac and Russia's Sputnik-V have been proven effective and successfully prevent COVID-19-related hospitalisation and mortality. Currently, all conventional COVID-19 vaccines are based on spike proteins and made on the reference genome of the SARS-CoV-2 virus (Wuhan-Hu-1). All vaccines are capable of inactivating and resisting alpha, beta, gamma, and delta variants of SARS-CoV-2. Due to the scarcity of vaccines, special attention needs to be paid to the immunisation programme as well as use of effective antiviral drugs, including ‘mAbs’, primarily to prevent COVID-19. An experimental antiviral pill 'Molnupiravir' that cuts the risk of hospitalization or death from Covid-19 by half would be the first oral antiviral medication for COVID-19, if approved by the US FDA for EUA.

‘Herd immunity’ is achieved when a large enough portion of a community is immune to a virus so that the virus can no longer spread easily from person to person. WHO says, ‘Herd immunity’ against COVID-19 should be achieved by protecting people through vaccination, not by exposing them to the pathogen that causes the disease. It is still unclear exactly how many people will need to be vaccinated in order to achieve herd immunity to COVID-19, but experts estimate that it will take at least 70% of the population. However, herd immunity against measles requires about 95% of a population to be vaccinated. So far (October 10, 2021), only 11.0 percent of the total population in Bangladesh are fully vaccinated. At least 70% or 112 million people in Bangladesh need to be vaccinated (in two doses) in order to achieve ‘Herd immunity’. Therefore, it is uncertain whether Bangladesh Government could provide vaccines on a large scale without producing its own vaccines. Thus, it is widely suggested that in addition to expanding the immunisation plan, a special attention should be paid to other effective antiviral drugs, including ‘‘mAbs’’ to prevent COVID-19.

Global access to ‘mAbs’ products are now severely limited to LMICs. Currently, commercial ‘mAbs’ are produced in mammalian Chinese Hamster Ovary (CHO) cells. It becomes very costly for its large scale culture and purification of ‘mAbs’. Therefore, efforts are underway to develop alternative production platforms aimed at how to produce low-cost ‘mAbs’, especially in LMICs that are suitable for transferring this technology. In particular, the use of transgenic plants, such as Tobacco plants, in the production of human ‘mAbs’ has raised hopes in LMICs. Using this technology, scientists have already produced monoclonal antibodies in transgenic tobacco plants that were shown to neutralise the rabies and Ebola viruses. Also, yeast, fungus, algae can be used as alternative platforms for the production of ‘mAbs’. However, the therapeutic value of the plant-derived product differs from the quality of the protein produced in the human body, as the enzymes required for the posttranslational modification (e.g., glycosylation) of their newly synthesised protein differ from plant to human. As a result, a humanised transgenic plant is created where the human enzyme (alpha 1, 4-galactosyltransferase) is produced, so that the limitation no longer exists.

Our expectation is that the leading pharmaceutical companies of Bangladesh will explore this opportunity using the alternative ‘molecular farming’ platforms to produce monoclonal antibodies on an urgent basis to prevent and treat multiple oncologic, rheumatoid arthritis, and many infectious diseases, including COVID-19.


The writers respectively are Former Pro-Vice Chancellor and Co-ordinator, Department of Pharmacy, Varendra University, Rajshahi