Structure-guided bispecific antibody engineering confers broad protection against KP.3.1.1 and sarbecoviruses.

ABSTRACT: The emergence of SARS-CoV-2 variants like KP.2 and KP.3.1.1 challenges COVID-19 countermeasures. Bispecific antibodies (bsAbs) targeting two antigens show promise, but the impact of scFv sequence arrangement on functionality remains unclear. Using neutralizing mAbs 7F3 (Omicron XBB.1-specific) and GW01 (cross-neutralizing), we engineered four bsAbs with diverse scFv configurations. Despite similar RBD binding affinities, only G7-Fc neutralized all 22 tested pseudoviruses, including KP.2, with 18-fold enhanced potency over S309. Cryo-EM revealed that G7-Fc uniquely stabilizes a BA.2.86 spike trimer-dimer apex-to-apex configuration, blocking RBD-ACE2 interaction via two conserved epitopes distinct from S309. Structure-guided A227S/T and Y229N mutations restored G7-Fc activity against KP.3.1.

SUBMITTER: Ma Y 

PROVIDER: S-EPMC12432451 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature