A recent study, currently available on the bioRxiv* preprint server, indicates that a pair of dual-action monoclonal antibodies derived from an original 2003 SARS survivor could play an important role in the fight against coronavirus disease 2019 (COVID-19) due to their broadly neutralizing activity and the engagement of the immune system via effector function capabilities.
The COVID-19 pandemic is still raging on, with substantial mortality rates in the elderly. Nonetheless, even in younger individuals that present with mild or moderate disease, there can be significant post-infection sequelae affecting overall health and resulting in long-term disability.
While different vaccines against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have already been authorized and used pervasively, the goal of swiftly reaching herd immunity may be hampered by supply issues, vaccine hesitancy, and the spread of viral variants. Likewise, those with underlying immunodeficiency may be at risk despite vaccination.
This means we need therapeutic approaches alongside preventive ones; accordingly, several types of monoclonal antibodies targeting SARS-CoV-2 spike glycoprotein have been authorized for use in the early treatment of COVID-19 patients, with clinical data showing promising results.
Nevertheless, rapidly spreading variants (including B.1.1.7 from the United Kingdom, B.1.351 from South Africa, and P.1 from Brazil) show reduced in vitro sensitivity to currently available antibodies that target the receptor-binding motif of the viral spike glycoprotein.
Hence, monoclonal antibodies targeting unique epitopes of the aforementioned spike glycoproteins will be needed in our therapeutic arsenal. And albeit viral neutralization is their main property, if they also have a potent effector function that elicits T cell immunity and aids in killing virally infected cells, this would substantially help in halting disease progression.
In this new research paper, a research group from Vir Biotechnology in San Francisco, California (USA) and Humabs Biomed SA in Bellinzona, Switzerland, aimed to appraise in vitro and in vivo activity of dual-function monoclonal antibodies against SARS-CoV-2.
Original SARS survivor as a source
In this study, two dual-action monoclonal antibodies, VIR-7831 and VIR-7832, were derived from the parent antibody S309 found in an original SARS-CoV survivor. They target an epitope containing a glycan that is highly conserved within the region of the S receptor-binding domain (RBD) that does not compete with angiotensin-converting enzyme 2 (ACE2) binding.
In order to determine the binding activity of these two monoclonal antibodies to the SARS-CoV-2 spike glycoprotein, the researchers used enzyme-linked immunosorbent assay (ELISA), flow cytometry and surface plasmon resonance (SPR) assays.
Finally, VIR-7831 and VIR-7832 were tested in a VeroE6 cell-based live SARS-CoV-2 virus system to test their neutralization propensity. The effector function potential of the antibodies has further been elucidated by antibody-dependent cellular phagocytosis (ADCP) and cytolysis (ADCC) assays by using donor peripheral blood mononuclear cells or natural killer cells.
Broad neutralization activity and immune engagement
In short, both tested antibodies showed high-affinity binding to spike glycoprotein in vitro (including on the cell surface) and effectively neutralized wild-type SARS-CoV-2 in a live virus assay. Furthermore, the experiments in the Syrian golden hamster model supported the proof-of-concept efficacy in vivo.
Both monoclonal antibodies harbor an “LS” mutation in the Fc region, which prolongs their half-life in the human serum and potentially enhances dissemination to the respiratory mucosa. Likewise, VIR-7832 encodes a specific mutation that was already linked with the induction of specific cellular immunity (i.e., CD8+ T-cells) in the context of an in vivo viral respiratory infection.
Importantly, both VIR-7831 and VIR-7832 retain activity against three mentioned SARS-CoV-2 viral variants in a VSV/VeroE6 pseudotyped virus system, which is consistent with recently published data. This is actually a key finding at this stage of the pandemic.
Finally, these monoclonal antibodies are able to recruit effector mechanisms in vitro that may contribute to clinical efficacy by eliminating infected host cells. In addition, conducted laboratory studies have shown no enhancement of infection.
A twofold effect against SARS-CoV-2
Taken together, this study indicates that VIR-7831 and VIR-7832 may indeed play a powerful role in our fight against COVID-19 through the dual action of their broad neutralizing activity and the engagement of the immune system by exploiting effector function capabilities.
“The potential for VIR-7832 to augment the T cell response to SARS-CoV-2 infection could conceivably play a crucial role in limiting progression to severe COVID-19 disease or in treatment of severe established disease”, further accentuate study authors in this bioRxiv paper.
In conclusion, additional studies will help translate these findings from bench to bedside of COVID-19 patients, which may benefit from the neutralization capacity of these antibodies that also harness the strength of our immune system.
bioRxiv 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.