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

• Published in: Human vaccines & immunotherapeutics 2024-12, Vol.20 (1), p.2388344
• Main Authors: Guerra, Denise, Radić, Laura, Brinkkemper, Mitch, Poniman, Meliawati, van der Maas, Lara, Torres, Jonathan L., Ward, Andrew B., Sliepen, Kwinten, Schinkel, Janke, Sanders, Rogier W., van Gils, Marit J., Beaumont, Tim
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Bispecific - immunology; Antibodies, Monoclonal - immunology; Antibodies, Neutralizing - immunology; Antibodies, Viral - immunology; bispecific antibodies; breadth; Coronavirus; COVID-19 - immunology; COVID-19 - prevention & control; cross-reactivity; Epitopes - immunology; Humans; neutralization; Neutralization Tests; sarbecoviruses; SARS-CoV-2; SARS-CoV-2 - immunology; Spike Glycoprotein, Coronavirus - immunology; variants
• ISSN: 2164-5515; 2164-554X; 2164-554X
• DOI: 10.1080/21645515.2024.2388344

Monoclonal neutralizing antibodies (mAbs) are considered an important prophylactic against SARS-CoV-2 infection in at-risk populations and a strategy to counteract future sarbecovirus-induced disease. However, most mAbs isolated so far neutralize only a few sarbecovirus strains. Therefore, there is a growing interest in bispecific antibodies (bsAbs) which can simultaneously target different spike epitopes and thereby increase neutralizing breadth and prevent viral escape. Here, we generate and characterize a panel of 30 novel broadly reactive bsAbs using an efficient controlled Fab-arm exchange protocol. We specifically combine some of the broadest mAbs described so far, which target conserved epitopes on the receptor binding domain (RBD). Several bsAbs show superior cross-binding and neutralization compared to the parental mAbs and cocktails against sarbecoviruses from diverse clades, including recent SARS-CoV-2 variants. BsAbs which include mAb COVA2-02 are among the most potent and broad combinations. As a result, we study the unknown epitope of COVA2-02 and show that this mAb targets a distinct conserved region at the base of the RBD, which could be of interest when designing next-generation bsAb constructs to contribute to a better pandemic preparedness.