New Monoclonal Antibody May Neutralize Future COVID-19 Variants

After monoclonal antibodies were proven less effective against the highly infectious Omicron COVID-19 variant, the US Food and Drug Administration (FDA) rescinded their approval of the therapy.

However, the clinical candidate antibody J08 may be able to prevent and treat COVID-19 present and future variants. In research published in the journal Proceedings of the National Academy of Sciences, investigators found J08 has low nanomolar affinity against most variants of concern (VoC) and binds high on the receptor binding domain (RBD) ridge, eluding most VoC mutations.

This study was a collaboration between Scripps Research and Toscana Life Sciences. The investigators studied the blood of 14 COVID-19 survivors, and J08 emerged as one of the most potent antibodies to combat the virus. J08 is now in stage 2/3 trials in Italy.

“Even though we can’t predict what variants of COVID-19 will emerge next, understanding the details of J08 reveals what works against the virus, and perhaps how we can engineer antibodies to be even more potent,” said Andrew Ward, PhD, a professor of integrative structural and computational biology at Scripps Research and a senior author of the study.

The investigators tested J08 for binding, ACE2 blocking, and neutralization with an enzyme-linked immunosorbent assay. They evaluated the neutralization activity of J08 using a lentiviral pseudovirus platform, including a COVID-19 spike variant including a cytoplasmic tail deletion of 19 amino acids. This pseudovirus platform enabled the investigators to test potential future COVID-19 variants.

The investigators found J08’s 3-dimentional structure successfully bound to the Alpha, Beta, Gamma, and Delta spike proteins, neutralizing these variants. J08 binds to a small section of the virus that remains consistent even as COVID-19 mutates. The investigators also found that J08 could attach in 2 completely different orientations.

However, J08 attached to Omicron almost 7 times more slowly, and then came off. Compared to the other tested variants, approximately 4000 times more J08 was needed to fully neutralize Omicron.

Omicron has 2 mutations, E484A and Q493H, that changed the small area of the virus to which J08 attaches. Notably, if just 1 of these mutations is present, J08 still binds and neutralizes the virus. Both of these mutations together, however, make Omicron so effective at evading monoclonal antibodies.

“I think we’re pretty confident that future variants won’t necessarily have both of these two critical mutations at the same time like Omicron,” said co-first author Gabiel Ozorowski, “so that makes us hopeful that J08 will continue being very effective.”

J08 outperformed similar RBD-binding competitor antibodies, including in its ability to neutralize Omicron with a high dosage. Cryo-EM and X-ray crystallography experiments revealed that J08 can bind to multiple versions of the S-protein.

J08 is currently being evaluated in clinical trials to test its ability to treat moderate-to-severe COVID-19 disease.