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Hum Vaccin Immunother
. 2024 Dec 31;20(1):2388344.
doi: 10.1080/21645515.2024.2388344. Epub 2024 Aug 20. Broadening sarbecovirus neutralization with bispecific antibodies combining distinct conserved targets on the receptor binding domain
Denise Guerra 1 2 , Laura Radić 1 2 , Mitch Brinkkemper 1 2 , Meliawati Poniman 1 2 , Lara van der Maas 3 , Jonathan L Torres 3 , Andrew B Ward 3 , Kwinten Sliepen 1 2 , Janke Schinkel 1 2 , Rogier W Sanders 1 2 4 , Marit J van Gils 1 2 , Tim Beaumont 1 2
Affiliations
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.
Keywords: SARS-CoV-2; bispecific antibodies; breadth; cross-reactivity; neutralization; sarbecoviruses; variants.
. 2024 Dec 31;20(1):2388344.
doi: 10.1080/21645515.2024.2388344. Epub 2024 Aug 20. Broadening sarbecovirus neutralization with bispecific antibodies combining distinct conserved targets on the receptor binding domain
Denise Guerra 1 2 , Laura Radić 1 2 , Mitch Brinkkemper 1 2 , Meliawati Poniman 1 2 , Lara van der Maas 3 , Jonathan L Torres 3 , Andrew B Ward 3 , Kwinten Sliepen 1 2 , Janke Schinkel 1 2 , Rogier W Sanders 1 2 4 , Marit J van Gils 1 2 , Tim Beaumont 1 2
Affiliations
- PMID: 39165108
- 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.
Keywords: SARS-CoV-2; bispecific antibodies; breadth; cross-reactivity; neutralization; sarbecoviruses; variants.