Two antibodies show broad, synergistic neutralization against SARS-CoV-2 variants by inducing conformational change within the RBD

Abstract

Continual evolution of the SARS-CoV-2 virus has allowed for its gradual evasion of neutralizing antibodies (nAbs) produced in response to natural infection or vaccination. The rapid nature of these changes has incited a need for the development of superior broad nAbs and/or the rational design of an antibody cocktail that can protect against the mutated virus strain. Here, we report two ACE2 competing nAbs—8H12 and 3E2—with synergistic neutralization but evaded by some Omicron subvariants. Cryo-EM reveals the two nAbs synergistic neutralizing virus through a rigorous pairing permitted by rearrangement of the 472-489 loop in the RBD to avoid steric clashing. Bispecific antibodies based on these two nAbs tremendously extend the neutralizing breadth and restore neutralization against recent variants including currently dominant XBB.1.5. Together, these findings expand our understanding of the potential strategies for the neutralization of SARS-CoV-2 variants toward the design of broad-acting antibody therapeutics and vaccines.

Broadening sarbecovirus neutralization with bispecific antibodies combining distinct conserved targets on the receptor binding domain

“…Most of the bsAb combinations produced in this study had retained or even increased binding strength to S proteins of different sarbecoviruses. Others have reported synergistic neutralization of SARS-CoV-2 variants combining broad class 4 mAbs with more specific class 1 mAbs 59 , and similarly to this study, class 3 and 4 mAbs 48,60 . Of note, in a previous study 48 , a mix of class 3 CV38-142 and class 4 COVA1-16 showed modest synergistic effects.…”