tetano
Editor, Senior Moderator
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[SUP] 1 2 [/SUP], Laura Radić[SUP] 1 2 [/SUP], Mitch Brinkkemper[SUP] 1 2 [/SUP], Meliawati Poniman[SUP] 1 2 [/SUP], Lara van der Maas[SUP] 3 [/SUP], Jonathan L Torres[SUP] 3 [/SUP], Andrew B Ward[SUP] 3 [/SUP], Kwinten Sliepen[SUP] 1 2 [/SUP], Janke Schinkel[SUP] 1 2 [/SUP], Rogier W Sanders[SUP] 1 2 4 [/SUP], Marit J van Gils[SUP] 1 2 [/SUP], Tim Beaumont[SUP] 1 2 [/SUP]
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[SUP] 1 2 [/SUP], Laura Radić[SUP] 1 2 [/SUP], Mitch Brinkkemper[SUP] 1 2 [/SUP], Meliawati Poniman[SUP] 1 2 [/SUP], Lara van der Maas[SUP] 3 [/SUP], Jonathan L Torres[SUP] 3 [/SUP], Andrew B Ward[SUP] 3 [/SUP], Kwinten Sliepen[SUP] 1 2 [/SUP], Janke Schinkel[SUP] 1 2 [/SUP], Rogier W Sanders[SUP] 1 2 4 [/SUP], Marit J van Gils[SUP] 1 2 [/SUP], Tim Beaumont[SUP] 1 2 [/SUP]
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.