US researchers have published a proof of concept on the efficacy of human monoclonal antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in laboratory conditions, as well as their pioneering use in a mouse model. The study is available on the preprint server bioRxiv*.
Basic virology research of SARS-CoV-2 is of utmost importance during coronavirus disease 2019 (COVID-19) pandemic; nonetheless, sufficient understanding fundamental immunological processes and body responses is crucial for identifying and designing effective treatment options.
Some preliminary reports have revealed potent inhibitory properties of inactivated serum from convalescent patients towards SARS-CoV-2 replication, decreasing in turn symptom severity of newly infected patients. This suggests that monoclonal antibodies may prove even more effective for this cause.
SARS-CoV-2 virus binding to ACE2 receptors on a human cell, the initial stage of COVID-19 infection. Illustration Credit: Kateryna Kon / Shutterstock
Human monoclonal antibodies as a potential solution
Human monoclonal antibodies are highly target-specific and relatively non-toxic. By using phage display (laboratory technique utilized for studying protein-ligand interactions), a number of potent human monoclonal antibodies against emerging viruses have already been identified – including SARS-CoV that caused the original SARS outbreak back in 2003.
Monoclonal antibodies have also been developed for the Middle East respiratory syndrome coronavirus (MERS-CoV) and bat-borne henipaviruses, which were also highly effective in animal models. One of them was even administered on a compassionate basis to humans exposed to henipaviruses, and subsequent evaluation in a clinical trial was successful.
The pertinent question in the midst of the COVID-19 pandemic is whether the same approach is possible for SARS-CoV-2. A group of researchers from the University of Pittsburgh Medical School, Galveston National Laboratory, the University of North Carolina at Chapel Hill, and Abound Bio in Pittsburgh (US) aimed to provide some answers.
Research informed by antibody libraries
In order to generate safe monoclonal antibodies with high affinity, these authors constructed eight extensive naive human antibody libraries (more than a thousand clones each) using peripheral blood mononuclear cells from a total of 490 individuals obtained well before the global spread of SARS-CoV-2.
Rather complex strategies were pursued to hunt for perfect antibody candidates. More specifically, four of the libraries were based on a single human heavy chain variable domain (VH), where complementarity-determining regions from other libraries were grafted in order to develop antibodies targeting SARS-CoV-2.
A microneutralization assay and a luciferase reporter gene assay were used to appraise neutralizing antibody activity. Moreover, to evaluate the efficacy of IgG1 fraction of antibodies in vivo, the researchers used transgenic mice that express the human ACE2 receptor utilized by the novel coronavirus for cell entry.
To further gauge the developability of the antibodies, their sequences were analyzed online, and any potential liabilities were excluded. In addition, dynamic light scattering and size exclusion chromatography were used to evaluate the propensity for aggregation.
Potent activity in laboratory and animal models
In short, IgG1 antibodies exhibited potent neutralizing activity in the two aforementioned laboratory assays. Even more importantly, there was clear evidence of the preventative antibody effect in mice.
"This is the first report of in vivo activity of a human monoclonal antibody against SARS-CoV-2", emphasize study authors the implications of their findings.
Interestingly, the antibody region that binds to antigen exhibited only several somatic mutations in comparison to the closest germline predecessor genes – suggesting that such antibodies could be elicited rather quickly with the use of immunogens based on SARS-CoV-2 receptor-binding domain.
"This is in contrast to the highly mutated broadly neutralizing HIV antibodies that require long maturation times, are difficult to elicit, and their germline predecessors cannot bind native HIV envelope glycoproteins," further explain study authors.
The germline-like trait of the newly identified monoclonal antibody also implies that it comes with exceptional developability properties that could expedite its development for prevention and treatment of COVID-19.
Multifaceted value of monoclonal antibodies
"The high affinity/avidity and specificity of IgG1 monoclonal antibody, along with potent neutralization of virus and good developability properties, suggests its potential use for prophylaxis and therapy of SARS-CoV-2 infection", say study authors.
Strong competition with human ACE2 is also due to a certain amount of mimicry, which means that mutations in the receptor-binding domain may also lead to inefficacious cell entry and subsequent infection.
However, in the unlikely case of mutations that would decrease the binding affinity of the antibody towards the aforementioned receptor-binding domain, a mixture of different monoclonal antibodies can be used.
"The identification of neutralizing monoclonal antibodies within days of target availability shows the potential value of large antibody libraries for rapid response to emerging viruses," conclude the authors.
An approach to monoclonal antibody development described in this study could also be used to select adequate epitopes for vaccine immunogens, as well as for swift diagnosis of SARS-CoV-2 infections in the future.
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
Li, W. et al. (2020). Potent neutralization of SARS-CoV-2 in vitro and in an animal model by a human monoclonal antibody. bioRxiv. https://doi.org/10.1101/2020.05.13.093088.