A multispecific antibody confers pan-reactive SARS-CoV-2 neutralization and prevents immune escape

Continued evolution of the SARS-CoV-2 spike poses a challenge to immune interventions. To develop antibodies that protect against evolving SARS-CoV-2 viruses, we combined antibodies that recognize different RBD sites to generate a trivalent antibody that potently neutralized all major variants, including the most recent Omicron lineages. Negative stain electron microscopy suggests that this multispecific achieves synergistic neutralization by engaging different epitopes in specific orientations that facilitate inter-spike binding. These interactions resulted in not only improved potency but also importantly prevented virus escape, a feature not seen with parental antibody cocktails or the most potent clinical antibody. Such multispecific antibodies simplify treatment, maximize coverage, decrease the likelihood of SARS-CoV-2 escape, and provide the basis for building universal SARS-CoV-2 antibody therapies that are more likely to maintain broad reactivity for future variants. One-Sentence Summary SARS-CoV-2 multispecific antibodies expand neutralization breadth and potency, prevent immune escape, and simplify treatment. ### Competing Interest Statement T.Z., L.W., J.M., A.P., Y.Z., E.S.Y., W.S., J.R.M, N.J.S., and P.D.K. are inventors on US patent application No. 63/147,419. R.R.W., Z-y.Y. and G.J.N are inventors on patent WO2017180913A. J.L., G.J.N., C-J.W., R.R.W., Z-y. Y. are employees of ModeX Therapeutics Inc., an OPKO Health Company. G.J.N., C-J.W, R.R.W. and Z-Y. Y. are inventors on US patent application Nos. 63/357,336 and 63/357,873. J.M., A.P., L.W., T.Z., M.C., O.K.O., B.Z., Y.Z., E.S.Y., M.C, K.L., W.S., N.J.S., J.R.M., P.D.K. and R.A.K. are inventors on the same application.