By Adriana Ramos Calvo
COVID-19, the disease caused by the novel virus SARS-CoV-2, is expanding rapidly, causing countries that had previously relaxed their precautionary measures to go back into lockdown and marking the development of treatment strategies as one of researchers’ top priorities. During these last months, a great deal of effort has been put towards fulfilling this objective, with the scientific community focusing on the identification of anti-viral molecules that target S proteins, molecules that play a crucial role in viral entry and replication in the host cell (Jahanshahlu and Rezaei, 2020). Despite coronaviruses having emerged several times, at regular intervals over the last decades, the consequent research on these viruses and the diseases they cause have thus far not led to the discovery of any vaccines, therapeutic agents or post-exposure prophylaxis treatments to prevent future epidemics (Shanmugaraj et al., 2020). SARS-CoV-2 retains structural, genetic, epidemiological and clinical similarities with SARS-CoV, and this has created potential for understanding the development of this disease and finding effective agents to treat and prevent COVID-19. One particular avenue of research, monoclonal antibodies, were proven to neutralize other coronaviruses, and this has consequently resulted in biotherapy being considered as a possible lead treatment for COVID-19 (Jahanshahlu and Rezaei, 2020).
Passive antibody therapy is being considered as a way to fight the pandemic by reducing viral replication and COVID-19 severity. This technique is performed using antibodies which recognize epitopic regions of the virus, and these such antibodies can be manufactured in a laboratory or isolated from the blood of affected individuals. Other viral infections such as Ebola, influenza and, most importantly, SARS and MERS provided evidence and experience in antibody therapy treatment. In particular, the early treatment of patients with convalescent plasma or hyper-immune immunoglobulin that contains significant antibody titers (how much antibody an organism has produced that recognizes a specific epitope), had emerged as a successful therapeutic treatment. However, the adoption of this technique with SARS-CoV-2 may be more difficult, as this virus poses some key challenges: the clinical condition of the patients, viral kinetics, and the availability of sufficient donors or host interactions of SARS-CoV-2, to name a few – these challenges need to be overcome before using the proposed antibody therapeutic option, to avoid the risk of further health complications (Shanmugaraj et al., 2020).
In response to invading viruses or other pathogens, the immune system naturally produces proteins that can be copied in a laboratory for therapeutic use: these are termed monoclonal antibodies (National Institute of Health, 2020). Using these antibodies within therapy to treat illnesses that compromise the immune system may help overcome many disadvantages of intravenous immunoglobulin preparations and serum therapy in relation to purity, contamination, specificity and safety (Shanmugaraj et al., 2020). As mentioned above, the target of coronavirus-neutralizing antibodies is, generally, the trimeric spike (S) glycoproteins on the viral surface, which are in charge of mediating the entry into host cells. The S protein has two functional subunits that are vital to cell attachment: the S1 subunit, conformed by four core domains, S1A through S1D; and the S2 subunit, fusion of the viral and cellular membrane. The receptor interaction site in S1 is a common target of potent neutralizing antibodies used in order to disable receptor interactions, which are known to cause irreversible conformational changes in the virus’ spike proteins, enabling membrane fusion (Wang et al., 2020).
Clinical trials are being carried out by investigators of the COVID-19 Prevention Network, recently established by the National Institute of Allergy and Infectious Diseases (NIAID) in the United States. These trials are Phase 3, randomized, placebo-controlled, double-blind clinical trials performed to test whether experimental monoclonal antibodies (mAbs) can prevent infection by the SARS-CoV-2 virus. These trials enrol adults that are at risk of infection due to close contact at either home or work to COVID-19 affected patients. One of these trials, conducted by Regeneron Pharmaceuticals and NIAID, will evaluate Regeneron’s investigational double mAb combination, REGN-COV-2, designed to bind to two points on the SARS-CoV-2 spike protein and therefore preventing its entrance to healthy cells. This study will be performed on 2,000 healthy adults who live in the same household as patients diagnosed with COVID-19 and who have been in contact with them in a 96-hour window preceding administration of either REGN-CoV-2 or placebo. This will be carried out to determine whether the mAb combination can prevent the infection or reduce the symptoms. The efficacy assessment will be a one-month period following administration; however, all trial participants will be followed for safety for seven months after this (National Institute of Health, 2020).
Considering the lack of effective therapeutic treatments or vaccines against the coronavirus infection, the main focus at present is the development of supportive care, and passive immunization may show itself to be useful in slowing down the progress of the COVID-19 pandemic (Jahanshahlu and Rezaei, 2020). Despite the major progress that has been made in the development of monoclonal antibody therapy, no monoclonal antibodies have yet been successfully marketed. COVID-19 therapeutic design might benefit from the existing antiviral regimen that showed promising results against MERS and SARS, yet further understanding of the virus’ origins and functioning, however, are necessary in order to design therapeutics specific to this novel coronavirus, and provide patients with greater treatment prospects (Shanmugaraj et al., 2020).
National Institute of Health (NIH). 2020. Clinical Trials Of Monoclonal Antibodies To Prevent COVID-19 Now Enrolling. [online] Available at: <https://www.nih.gov/news-events/news-releases/clinical-trials-monoclonal-antibodies-prevent-covid-19-now-enrolling> [Accessed 10 October 2020].
Jahanshahlu, L. and Rezaei, N., 2020. Monoclonal antibody as a potential anti-COVID-19. Biomedicine & Pharmacotherapy, 129, p.110337.
Shanmugaraj, B., Siriwattananon, K., Wangkanont, K. and Phoolcharoen, W., 2020. Perspectives on monoclonal antibody therapy as potential therapeutic intervention for Coronavirus disease-19 (COVID-19). Asian Pac J Allergy Immunol, 38(1), pp.10-18.
Wang, C., Li, W., Drabek, D., Okba, N., van Haperen, R., Osterhaus, A., van Kuppeveld, F., Haagmans, B., Grosveld, F. and Bosch, B., 2020. A human monoclonal antibody blocking SARS-CoV-2 infection. Nature Communications, 11(1).