The ongoing COVID-19 pandemic has become a major source of disruption and upheaval to normal daily routines. The repeated opening and re-shuttering of schools and universities in response to spiking case numbers, for example, highlights the need for preventative treatments before a return to normalcy is possible.
While vaccines are being developed, other prevention and treatment options, such as neutralizing antibodies, are an area of intense interest.
In a previous post, we discussed a study by Rebecca Powell suggesting that breastmilk from lactating mothers who have recovered from SARS-CoV-2 infection may contain protective antibodies with therapeutic potential. That small, pilot study found that the predominant antibody response in milk was from secretory IgA (sIgA), not IgG, but the mechanism by which sIgA was able to promote protection against SARS-CoV-2 was not clear. Both sIgA and IgG are also present in the lung mucosa, where sIgA can act as a first line of defense, but the respective contributions of mucosal IgG and IgA to SARS-CoV-2 protection remains an open question.
With this in mind, we were excited to read a new study, authored by Ejemel and colleagues and titled “A cross-reactive human IgA monoclonal antibody blocks SARS-CoV-2 spike-ACE2 interaction,” published August 21 in the journal Nature Communications.
The research group, which represents a collaboration between University of Massachusetts Medical School, the National Infection Service of Public Health England, and Boston University, has identified a role and potential mechanism of action for sIgA in SARS-CoV-2 by comparing the functionality of IgG and IgA isotypes of a SARS-CoV-2 specific monoclonal antibody (mAb).
Monoclonal antibodies are particularly attractive as a SARS-CoV-2 treatment due to their relatively long half-lives in circulation (around 3 weeks for IgG1), suggesting that a single infusion could sufficiently halt disease progression. Although the monomeric IgA found in plasma has a relatively short half-life compared to IgG, the dimeric, the secretory form of IgA found in the lung mucosa is more stable.
sIgA could conceivably confer effective, localized immunity within the respiratory mucosa—the primary tissue in which SARS-CoV-2 infection takes hold.
Several neutralizing mAbs against SARS-CoV-2 have been developed that can inhibit interactions between the viral receptor binding domain (RBD) and the human cell-surface receptor, angiotensin-converting enzyme 2 (ACE2). This disruption has been shown to prevent membrane fusion and viral entry. To understand the difference between IgG and IgA isotypes of SARS-CoV-2 mAbs, the team inserted the variable regions from a mAb previously shown to inhibit SARS-CoV-2 into either an IgG or IgA expression vector. They then characterized the two new antibody isotypes’ viral-protein binding affinities and their viral-neutralization potency.
The authors found that, while both mAb isotypes successfully bound the viral RBD and interfered with its ACE2-receptor interaction, the IgA antibody displayed significantly greater neutralization potency, particularly when expressed in secretory form.
Structural studies indicated that the long hinge region in IgA conferred a flexibility not found in IgG, potentially enabling IgA to contact more epitopes on the viral RBD compared to the more rigid IgG molecule. This work identifies an important role for IgA in SARS-CoV2 neutralization and suggests a new avenue of investigation into the therapeutic potential of IgA antibodies.
The promising work by these groups and others suggests a pressing need to improve methods of sIgA production.
These findings are preliminary, of course, and the clinical safety and efficacy of sIgA-based therapies against COVID-19 remains to be demonstrated. In the meantime, there are significant barriers to overcome to before sIgA antibodies can be produced at therapeutic scale. Purifying them from breastmilk is infeasible and fraught with logistical and ethical challenges. Mammalian cell-culture systems have been optimized for expression of the smaller IgG proteins but not large, polymeric and post-translationally modified sIgA. The development of a scalable approach for sIgA production will represent a significant advance in our toolbox of methods for combating SARS-CoV-2 and potentially many other diseases.