Deciphering a reliable synergistic bispecific strategy of rescuing antibodies for SARS-CoV-2 escape variants, including BA.2.86, EG.5.1, and JN.1

The game between therapeutic monoclonal antibodies (mAbs) and continuously emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants has favored the virus, as most therapeutic mAbs have been evaded. Addressing this challenge, we systematically explored a reproducible bispecific antibody (bsAb)-dependent synergistic effect in this study. It could effectively restore the neutralizing activity of the bsAb when any of its single mAbs is escaped by variants. This synergy is primarily attributed to the binding angle of receptor-binding domain (RBD)-5, facilitating inter-spike cross-linking and promoting cryptic epitope exposure that classical antibody cocktails cannot achieve. Furthermore, RBD-5 with RBD-2, RBD-6, and RBD-7, alongside RBD-8, also exhibit significantly enhanced effects. This study not only shifts the paradigm in understanding antibody interactions but paves the way for developing more effective therapeutic antibodies against rapidly mutating SARS-CoV-2, with Dia-19 already showing promise against emerging variants like BA.2.86, EG.5.1, and JN.1. [Display omitted] •A bsAb construction utilizing synergistic effects to rescue parental mAbs escaped by variants•The scDb format combining RBD-8 and RBD-5 antibodies accelerates the exposure of RBD-8•Narrow antigen-binding site spans are crucial for replicating synergistic effects•RBD-5 scDb combinations with RBD-2, RBD-4, RBD-6, and RBD-7 exhibit similar effects Tong et al. systematically explore a bispecific antibody (bsAb)-dependent synergistic effect that can effectively restore the neutralizing activity of the bispecific antibody when individual monoclonal antibodies (mAbs) are evaded by variants. They show that this synergistic effect can salvage more escaped antibodies when certain prerequisites for the narrower antigen-binding site span, such as scDbs, and the correct antibody combinations are met.