A preprint of a study conducted by researchers from Utrecht University, in collaboration with Erasmus MC and Harbor BioMed, outlines the first report of a human monoclonal antibody that can block SARS-CoV-2.
Understanding antibodies: Terms and definitions
Antibodies are proteins that are produced by certain cells of the immune system known as B cells. They are able to bind to "foreign" material that tries to invade the body, such as pathogens, and directly neutralize them or trigger an immune response. This is achieved by binding of the antibody to an antigen, a specific molecule present on the pathogen.
Scientists are now able to create antibodies that target one specific antigen. These are known as monoclonal antibodies and they can be produced in large quantities in a laboratory setting. They can be utilized for a variety of different purposes, such as diagnostic tests and targeted treatment. There are several types of monoclonal antibody. A "human" monoclonal antibody is one that is entirely derived from a human source.
Monoclonal antibody potently inhibits SARS-CoV-2
SARS-CoV-2 and SARS-CoV both belong to the Sarbecovirus subgenus of the Coronaviridae family. The trimeric spike (S) glycoproteins present on the viral surface enable entry of the virus into host cells by binding to a receptor protein known as the human angiotensin converting enzyme (ACE2). Here, a "syringe" like mechanism enables injection of the viral genetic material into the cell, which is then replicated.
The spike proteins of SARS-CoV-2 and SARS-CoV are very similar on a structural level, sharing 77.5% of their amino acid sequence. Blocking the initial binding of the virus to the ACE2 receptor via the spike protein is one potential treatment avenue. Here's where monoclonal antibodies could help.
Monoclonal antibodies that target vulnerable sites on viral surface proteins are an emerging approach for treating infectious diseases. In this study by Wang et al., a human antibody known as 47D11 was found to bind to SARS-CoV-2 and SARS-CoV, and to potently inhibit the virus' infection of Vero cells, a type of cell line.
An unexpected mechanism of action
The antibody was discovered by Wang and colleagues using an ELISA-(cross)reactivity approach, assessing antibody-containing supernatant derived from transgenic mice. Upon discovery that the molecule 47D11 displayed ELISA-cross-reactivity with the SARS spike protein subunits from both SARS-CoV and SARS-CoV2, it was reformatted and expressed as a fully human IgG1 isotope antibody for further study.
How exactly does 47D11 neutralize coronavirus? The scientists aren't too sure yet. However, it appears that it's not by preventing the S protein from binding to ACE2, interestingly.
The authors say in the preprint: "Our data show that 47D11 neutralizes SARS-CoV and SARS-CoV-2 through a yet unknown mechanism that is different from 86 receptor binding interference. Alternative mechanisms of coronavirus neutralization by receptor binding domain-targeting antibodies have been reported including spike inactivation through antibody-induced destabilization of its prefusion structure, which may also apply for 47D11."
They continue: "47D11 binds a conserved epitope on the spike receptor binding domain explaining its ability to cross-neutralize SARS-CoV and SARS-CoV-2, using a mechanism that is independent of receptor binding inhibition."
"Far too early to speculate"
It's important to note that the study remains to be peer-reviewed and is not yet published in a journal. Therefore, the scientists behind the research heed caution in making overzealous assumptions based on the preprint. A press release from Utrecht University says:
Research leader and last author Berend-Jan Bosch (Utrecht University) does not want to raise false expectations. It is a promising first step, but it is far too early to speculate about the potential efficacy in humans. The research is being reviewed by a leading scientific journal. Further comments can be provided once the item has been accepted.
It's early days, but it's apparent that further research is certainly warranted here. The scientists conclude the discussion section of the preliminary report by saying: "Neutralizing antibodies can alter the course of infection in the infected host supporting virus clearance or protect an uninfected host that is exposed to the virus. Hence, this antibody offers the potential to prevent and/or treat COVID-19, and possibly also other future emerging diseases in humans caused by viruses from the Sarbecovirus subgenus."
Reference: Wang et al. (2020). A human monoclonal antibody blocking SARS-CoV-2 infection. bioRxiv. https://doi.org/10.1101/2020.03.11.987958