Clinical Progress of Anti-SARS-CoV-2 Neutralizing Antibody (NAb)—PART I

Currently, the number of COVID-19 confirmed cases has exceeded 147 million, and the death exceeded 2 million. The rapid spread of COVID-19 prompts the healthcare community to explore potential treatments, by investigating the drugs that are already approved and developing innovative therapies simultaneously such as antiviral drugs and passive immunotherapy. Anti-inflammatory monoclonal antibodies (mAbs) have been used to control the cytokine storm, and the results varied. However, the therapeutic effects of the convalescent plasma (CP) treatment have brought higher expectations, of which the active substances are polyclonal neutralizing antibodies. Although the efficacy of CP has been questioned due to the lack of standardized doses and the poor results of nAbs obtained from virus neutralization tests, the positive preliminary results have promoted the R&D of immune serum and neutralizing monoclonal antibodies (https://www.creativebiolabs.net/neutralizing-antibodies_68.htm). NAbrnCompared with CP and immune serum, neutralizing antibodies pose certain advantages since the number of therapeutic antibodies is limited to one or two. (a) The most effective candidate antibody can be selected, with IC50 in nanomolar or even picomolar level. (b) The dose of neutralizing antibodies is easier to be evaluated. (c) The so-called antibody-dependent enhancement (ADE) can be eliminated Neutralizing antiviral mAbs have been successfully used in clinical practices against the respiratory syncytial virus (RSV) and Ebola virus (EBOV). Neutralizing monoclonal antibodies extracted from recovered patients. Generally speaking, extracting neutralizing antibodies from recovered patients includes several steps, which are selecting peripheral blood mononuclear cells from CP donors, isolating receptor-binding domain (RBD) specific single memory B lymphocytes, cloning, transfection, and finally antibody preparation. Through this method, many monoclonal antibodies with potential neutralizing activity against SARS-CoV-2 have been discovered. Currently, 14 mAbs or mAb combinations have entered clinical trials, with five drugs entered the Phase II stage. VIR-7831rnVIR-7831 (also known as GSK4182136) is a fully human anti-SARS-CoV-2 monoclonal antibody developed jointly by VIR Biotechnology and GSK, derived from S309 (https://www.creativebiolabs.net/anti-sars-cov-2-2019-ncov-s-rbd-recombinant-antibody-clone-s309-137710.htm), which was identified from patients who recovered from SARS in 2003, and has also been proven to neutralize SARS-CoV-2. It binds to a highly conserved epitope shared by the two coronaviruses. That epitope is located on the spike protein and is used by the virus to bind and enter human cells to cause infection. VIR-7831 improves the pharmacokinetic properties, especially the prolonged half-life. It is worth noting that the second antibody, named VIR-7832, is under development and has the same principle, which, however, is designed as a T cell vaccine that can recruit T lymphocytes and then recognize and kill SARS-CoV-2 infected cells. VIR-7831 clinical research is currently being conducted on patients with early COVID-19 infection, who have high risk of hospitalization (i.e., patients at/or over 55 years of age with lung or cardiovascular disease). The purpose of the COMET-ICE trial (NCT04545060) is to recruit 20 patients with early-symptomatic COVID-19 in the introductory phase and approximately 1,300 patients in the dilated phase globally. The primary endpoint is the proportion of patients with COVID-19 progression on day 29, and the secondary endpoints involve the incidence of adverse events and the production and titer of anti-drug antibodies (ADAs) to VIR-7831. The final report is scheduled to be published in July 2021. If the expectation can be achieved, the drug will be on the market in the first quarter of 2021.