Highlights

Above

Anti-SARS-CoV-2 antibodies have varying effects. For instance, only 5A6 IgG antibodies (upper left) inhibit spike-mediated cell fusion, whereas the other receptor-blocking antibodies failed to inhibit or even enhance this process.

© Wang Bei, Hu Yuanyu and Wang Cheng-I

Not all antibodies are created equal

10 Sep 2021

Some neutralizing antibodies against SARS-CoV-2 may heighten lung tissue damage from COVID-19, an A*STAR study finds.

As part of the body’s frontline defense against microbial enemies, neutralizing antibodies have been thrust in the spotlight for their potential to treat COVID-19. Now, research led by Cheng-I Wang, a Principal Investigator at A*STAR’s Singapore Immunology Network (SIgN), has uncovered a darker side to some of these immune heroes.

Previously, Wang and colleagues demonstrated that most neutralizing antibodies block the SARS-CoV-2 spike protein’s receptor-binding domain (RBD) from interacting with ACE2 receptors on
host cells. However, the influence of these antibodies on the generation of syncytia—cell fusions associated with severe COVID-19 symptoms—has remained a gray area.

“The formation of syncytia has been linked to lung tissue damage observed in severe COVID-19 cases when cell-cell fusion occurs inside the patient’s airways,” explained Wang, adding that clearer guidelines for selecting neutralizing antibodies as treatments for COVID-19 patients with severe lung damage are urgently needed.

In a study published in Cell, Wang teamed up with collaborators to analyze a panel of six antibodies for factors that may impact SARS-CoV-2 neutralization potency and syncytia formation. These include properties such as how strongly the antibody binds to its target and where the antibody binds to the spike protein.

As predicted, all six antibodies blocked interactions between the SARS-CoV-2 spike protein and ACE2 receptors, but unexpectedly displayed a range of responses to syncytia formation.

An antibody called 3D11, for instance, displayed the strongest binding to the spike protein’s RBD—which by current standards, would suggest potential therapeutic value. Interestingly, however, 3D11 attaches to the RBD at a site that locks the spike protein in an ‘open’ pre-binding position, effectively accelerating interactions between the spike protein and ACE2 as well as promoting syncytia formation.

Conversely, the 5A6 antibody bound less strongly to the spike protein, but was far more potent, latching onto the RBD and strongly inhibiting syncytia development. A closer look at the structural dynamics of 5A6 binding to the RBD revealed that the antibody recognized an exposed loop near the tip of the RBD, trapping the spike protein in its ‘closed’ position, thereby hindering ACE2 binding.

“These findings suggest that the potential effectiveness of a neutralizing antibody is influenced by several possibly countervailing factors, highlighting a complex basis for viral neutralization potency,” Wang concluded. The team is now looking to partner with industry collaborators to commercialize the 5A6 antibody as a viable candidate for COVID-19 treatment.

The A*STAR-affiliated researchers contributing to this research are from the Singapore Immunology Network (SIgN).

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References

Asarnow, D., Wang, B., Lee, W.H., Hu, Y., Huang, C.W., et al. Structural insight into SARS-CoV-2 neutralizing antibodies and modulation of syncytia. Cell 184, 3192–3204.e16 (2021) | article

About the Researcher

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Cheng-I Wang

Principal Investigator

Singapore Immunology Network
Cheng-I Wang received a PhD degree in chemistry from Washington University and completed his postdoctoral training in the department of pharmaceutical chemistry at the University of California, San Francisco. Wang worked on drug discovery projects at biotechnology and pharmaceutical companies in the US before joining the A*STAR Singapore Immunology Network (SIgN) in 2009. As Head of the Human Monoclonal Antibody Technology Platform at SIgN, Wang works on the discovery and development of human antibodies against infection and immune disorders, using combinatorial approaches to incorporate novel functions into protein and antibody molecules.

This article was made for A*STAR Research by Wildtype Media Group